Fused heterocyclic compounds as ion channel modulators

ABSTRACT

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein Q, R 1 , X 1 , X 2 , Y and R 2  are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.Nos. 61/484,500, filed on May 10, 2011 and 61/503,543, filed on Jun. 30,2011, the entirety of which are incorporated herein by reference.

FIELD

The present disclosure relates to novel compounds and to their use inthe treatment of various diseases, including cardiovascular diseases anddiabetes. The disclosure also relates to methods for preparation of thecompounds and to pharmaceutical compositions containing such compounds.

BACKGROUND

The late sodium current (INaL) is a sustained component of the fast Na+current of cardiac myocytes and neurons. Many common neurological andcardiac conditions are associated with abnormal INaL enhancement, whichcontributes to the pathogenesis of both electrical and contactiledysfunction in mammals. See, for example, Pathophysiology andPharmacology of the Cardiac “Late Sodium Current”, Pharmacology andTherapeutics 119 (2008) 326-339. Accordingly, compounds that selectivelyinhibit INaL in mammals are useful in treating such disease states.

One example of a selective inhibitor of INaL is RANEXA®, a compoundapproved by the FDA for the treatment of chronic stable angina pectoris.RANEXA® has also been shown to be useful for the treatment of a varietyof cardiovascular diseases, including ischemia, reperfusion injury,arrhythmia, unstable angina, and diabetes. It would be desirable toprovide novel compounds that selectively inhibit INaL in mammals andthat have the same selectivity over peak INa inhibition as RANEXA®.

SUMMARY

Accordingly, in some embodiments the present disclosure provides novelcompounds that function as late sodium channel blockers. In oneembodiment, is provided compounds of Formula I:

wherein:

the dotted line represents an optional double bond;

-   -   Y is —C(R⁵)₂— or —C(O)—;    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CR³ and X²        is N, and the dotted line is a double bond; or    -   X¹ is C(R³)₂ and X² is NR⁴, —O—, —S—, —S(O)— or —S(O)₂—, or X¹        and X² are both C(R³)₂, and the dotted line is a single bond;        -   provided that:        -   when the dotted line is a single bond and Y is —C(R⁵)₂—;            then both X¹ and X² are C(R³)₂; and        -   when the dotted line is a double bond; Y is —C(O)—;    -   Q is a covalent bond or C₂₋₄ alkynylene;    -   R¹ is C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, heterocyclyl or        heteroaryl;    -   wherein said C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl,        heterocyclyl or heteroaryl are optionally substituted with one,        two or three substituents independently selected from the group        consisting of halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆            cycloalkyl, —N(R²⁰)(R²²), —C (O)—R²⁰, C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —R⁶, —C₁₋₆ alkylene-R⁶, —C₂₋₆ alkenylene-R⁶, —C₂₋₆        alkynylene-R⁶, -L-R⁶, -L-C₁₋₆ alkylene-R⁶, —C₁₋₆ alkylene-L-R⁶        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁶;    -   L is —O—, —S—, —C(O)—, —S(O)₂—, —NR²⁰S(O)₂—, —S(O)₂NR²⁰—,        —C(O)NR²⁰— or —NR²⁰C(O)—; provided that when Y is —C(R⁵)₂₋, then        L is C(O)— or —S(O)₂₋₅ and R² is -L-R⁶, -L-C₁₋₆ alkylene-R⁶,        —C₁₋₆ alkylene-L-R⁶ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁶;    -   each R³ is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₃₋₆ cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl,                    aryl, heterocyclyl and heteroaryl are optionally                    further substituted with one, two or three                    substituents independently selected from the group                    consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    C(O)—OR²⁰, —C)(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when X¹ is C(R³)₂, two R³ can join together with the with the        carbon atom to which they are attached to form a C₃₋₆ cycloalkyl        or heterocyclyl;    -   R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, —C(O)—OR²⁰,        —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰, C₃₋₆ cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₃₋₆ cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl,                    aryl, heterocyclyl, heteroaryl, are optionally                    further substituted with one, two or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —N(R²⁰)(R²²),                    —C(O)—R²⁰, —C(O)—OR²⁰, —C)(O)—N(R²⁰)(R²²), —CN and                    —O—R²⁰;    -   each R⁵ is independently hydrogen or C₁₋₆ alkyl;    -   R⁶ is C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₃₋₆ cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂, C₃₋₆            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)— C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰, —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —NO₂, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)R²⁰,                —C(O)—OR²⁰, —C(O)—N(R²⁰) (R²²), —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    C₁₋₆ alkyl, halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²),                    —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN,                    S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently hydrogen, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,        heterocyclyl, aryl or heteroaryl; and        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, aralkyl, —N(R²⁶)(R²⁸),            aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, —C(O)—R²⁶, —C(O)—OR²⁶, aryl, C₃₋₆            cycloalkyl, heterocyclyl, aryl and heteroaryl;            -   wherein said aralkyl, heterocyclyl or heteroaryl is                optionally further substituted with C₁₋₄ alkyl, —CF₃,                aryl or C₃₋₆ cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, heteroaryloxy,        substituted amino, aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃        alkoxy, hydroxymethyl, —CF₃, —OCF₃, aryl, heteroaryl and C₃₋₆        cycloalkyl; and    -   R²⁶ and R²⁸ are each independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₃₋₆        cycloalkyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl or heteroaryl            may be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃, —OCF₃ and C₃₋₆            cycloalkyl;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

Some embodiments provide a method of using the compounds of Formula I inthe treatment of a disease or condition in a mammal that is amenable totreatment by a late sodium channel blocker. The compounds of thedisclosure and their pharmaceutically acceptable salt, ester, hydrate,solvate, stereoisomer, tautomer, polymorph and/or prodrug forms arepotentially of use as medicaments for the treatment of certain diseases,such as, cardiovascular diseases such as atrial and ventriculararrhythmias, heart failure (including congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure),Prinzmetal's (variant) angina, stable and unstable angina, exerciseinduced angina, congestive heart disease, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease, and intermittent claudication. Suchdiseases may also include diabetes and conditions related to diabetes,e.g. diabetic peripheral neuropathy. Such diseases may also includeconditions affecting the neuromuscular system resulting in pain,seizures, or paralysis.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I) and at least onepharmaceutically acceptable excipient.

In certain embodiments, the disclosure provides:

-   II-3    3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-4    3((5-chloropyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-6    3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-7    3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-phenoxyphenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-10    3-((3-phenylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-12    3-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-13    3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-14    3-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-15    3-(2-(pyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-16    6-(4-(4-chlorophenoxyl)phenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-17    3-(2-(pyrimidin-4-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-18    3-(2-(pyrimidin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-21    3-((5-phenyl-1H-tetrazol-1-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-22    3-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-23    3-((4,5-dimethyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-24    3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-25    3-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-26    3-((5-methylisoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-28    3-((2H-benzo[d][1,2,3]triazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-29    3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-32    3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-33    1-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)cyclopropanecarbonitrile-   II-34    3-((1-((2-methyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-36    2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)ethoxy)pyrimidine-4-carbonitrile-   II-38    3-(piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-39    3-(1-(pyrimidin-2-yl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-40    3-((1-(morpholinomethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-41    3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-42    3-benzyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-44    3-((4,6-dimethoxypyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-47    3-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-50    1-(4-(4-oxo-3-(2-(pyrimidin-2-yloxy)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)phenyl)cyclopropanecarbonitrile-   II-51    2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)ethoxy)pyrimidine-5-carbonitrile-   II-52    6-(4-(trifluoromethoxy)phenyl)-3-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-53    3-(1-(3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-54    3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-55 methyl    1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)methyl)cyclopropanecarboxylate-   II-56    3-(pyrimidin-2-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-57    3-((1-((2-ethyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-58    3-((1-((1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-59    3-(pyridin-3-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-60    3-(2-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-63    3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-64    3-((1-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-65    6-(4-(4-chlorophenoxyl)phenyl)-3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-66    3-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-67    3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-71 3-(1-(2″ 2    2-trifluoroethyl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-72 ethyl    4-oxo-3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)piperidine-1-carboxylate-   II-73    6-(4-cyclopropylphenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-75    3-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-79    3-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-80    3-((1-((pyrimidin-2-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-84    3-(2,2-dimethyl-3-(pyrimidin-2-yloxy)propyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-95    3-((2-methyloxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-96    3-((5-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-97    3-((4-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-98    3((2-cyclobutyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-99    3-((2-methyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   II-100    3((2-cyclopropyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one-   V-2 3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(6-(2,2,2-trifluoro    ethoxy)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one-   V-11    3-(2-(pyrimidin-2-yloxy)ethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one-   V-12    6-(2-(piperidin-1-yl)pyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one-   VII-1    3-(2-(pyrimidin-2-yloxy)ethyl)-6((4-(trifluoromethoxy)phenyl)ethynyl)benzo[d][1,2,3]triazin-4(3H)-one-   III-2    2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-3    2-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-5    2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-6 2-benzyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-8 2-phenethyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-9    2-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-10    2-(2-(1H-pyrrol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one-   III-11    2-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-12    6-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)picolinonitrile-   III-14    2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-17    2-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-18 2-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)p    henyl)phthalazin-1 (2H)-one-   III-19    2-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-20    2-(2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-22    2-(4,6-dimethylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-23    2-((4-cyclopropylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-24    2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-25    2-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-26    2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-27    2((4-(cyclopropylmethoxy)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-28    2-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-29    2-(2-(4-cyclopropylpyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-30    2-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-31    2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-32    2-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-34    2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-35    2-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-36    2-(2-(pyrimidin-4-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-37    2-(2-(5-chloropyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-38    2-(2-(1H-pyrazol-1-yl)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-39    2-(2-(pyrazin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-40    2-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   III-41    2-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one-   IV-3    3-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one-   IV-6    3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one-   IV-9    3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one-   VIII-1    3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-3    3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-7    2-methyl-3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-13    2,2-dimethyl-3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-18    6-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-19    3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-20    3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-21    3-benzyl-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-22    3-benzyl-6-(2-fluoro-4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   VIII-23    3-benzyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one-   X-1    3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-2    3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-3    3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-4    3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-5    3-(2-chlorobenzyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-6    3-((3-fluoropyridin-2-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   X-9    3-((3-fluoropyridin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one-   IX-1    2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one-   IX-2    2-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one-   IX-3    2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one-   IX-4    2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one-   IX-5    2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one-   IX-6    pyridin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-7    pyrimidin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-11    pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-17    pyridazin-3-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-22    (7-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone-   IX-23    (7-(4-chloro-2-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone-   IX-24    (7-(4-chloro-3-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone-   IX-25    (3-fluoropyridin-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-26    (7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone-   IX-27    (1-isopropyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-28    (1,3-dimethyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-29    2-(pyridin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone-   IX-30    2-(pyrimidin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone-   IX-31    (2-isopropylpyrimidin-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-32    pyrimidin-4-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-33    pyrimidin-5-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-34    (2-amino-6-methylpyrimidin-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-36    (1H-pyrazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-39    (1-methyl-1H-imidazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-41    N-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-42    N-phenyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-44    N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-48    N-(furan-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-50    N-methyl-N-phenyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-52    morpholino(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-53    pyrrolidin-1-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-56    (1-methyl-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-57    (1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-59    (4-fluoro-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-77    N-cyclopentyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-80    (1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-88    azetidin-1-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-89    N-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide-   IX-90    (3-methylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-91    (3-hydroxypyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-92    (3,3-difluoroazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-93    (3-(pyridin-3-yloxy)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-94    (3-fluoropyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-95    (3-fluoroazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-98    2-(1-methyl-1H-imidazol-4-ylsulfonyl)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-   IX-101    (R)-(3-(hydroxymethyl)pyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-102    (S)-(2-(hydroxymethyl)pyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-104    (3-(methylsulfonyl)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-105    ((2R,5R)-2,5-dimethylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-106    ((2R,5S)-2,5-dimethylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-107    (3-methylazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-108    (3-hydroxyazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-111    (3-amino-1H-1,2,4-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-112    (3-hydroxy-3-methylazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-113    (3-(hydroxymethyl)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-114 (R)-tert-butyl    2-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carboxylate-   IX-116    (1-phenyl-1H-1,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-119 ethyl    2-(4-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)acetate-   IX-122    pyrrolidin-1-yl(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone-   IX-123    N-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

DETAILED DESCRIPTION 1. Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,        —SO-cycloalkyl, —SO— heterocyclyl, —SO-aryl, —SO-heteroaryl,        —SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and        —SO₂-heteroaryl. Unless otherwise constrained by the definition,        all substituents may optionally be further substituted by 1, 2        or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3, 4, 5 or 6 carbon atoms.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl. This term is exemplified by groupssuch as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,t-butoxy, n-hexyloxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is substituted alkylene and Z issubstituted alkenyl or substituted alkynyl, where substituted alkyl,substituted alkenyl and substituted alkynyl are as defined herein.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “susbstituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO— cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl. The term “substituted cycloalkyl” also includescycloalkyl groups wherein one or more of the annular carbon atoms of thecycloalkyl group has an oxo group bonded thereto. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl —O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— cycloalkyl, —SO-heterocyclyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl,—SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl,—SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Examples of heterocyclics include tetrahydrofuranyl,morpholino, piperidinyl, and the like.

The term “heterocyclooxy” refers to the group O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl, benzothiazole orbenzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group S-substitutedalkyl.

The term “heterocyclylthio” refers to the group S-heterocyclyl.

The term “arylthio” refers to the group S-aryl.

The term “heteroarylthiol” refers to the group S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group S(O)₂NRR, wherein each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

The phrase “the dotted line is a double bond” refers to compounds ofFormula I having a double bond between X¹ and X². The phrase “the dottedline is a single bond” refers to compounds of Formula I having a singlebond between X¹ and X².

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given formula (e.g. the compound of Formula I, whichalso includes Formulas II, III, IV, V, VI, IA, IB, IC, ID, IIA, IIIA,IVA, IVB, VA, VIA, VIIA, VIIIA and IXA) is intended to encompass thecompounds of the disclosure, and the pharmaceutically acceptable salts,pharmaceutically acceptable esters, isomers, tautomers, solvates,isotopes, hydrates, polymorphs, and prodrugs of such compounds.Additionally, the compounds of the disclosure may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given formula depends upon the numberof asymmetric centers present (there are 2^(n) stereoisomers possiblewhere n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis orby resolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present disclosure, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.Non-limiting examples of amide-comprising and imidic acid-comprisingtautomers are shown below:

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “solvate” refers to a complex formed by the combining of acompound of Formula I, or any other formula as disclosed herein, and asolvent.

The term “hydrate” refers to the complex formed by the combining of acompound of Formula I, or any formula disclosed herein, and water.

The term “prodrug” refers to compounds of Formula I, or any formuladisclosed herein, that include a chemical groups which, in vivo, can beconverted and/or can be split off from the remainder of the molecule toprovide for the active drug, a pharmaceutically acceptable salt thereofor a biologically active metabolite thereof.

Any formula or structure given herein, including Formula I, or anyformula disclosed herein, is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶ Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also included compounds of Formula I, or any formuladisclosed herein, in which from 1 to “n” hydrogens attached to a carbonatom is/are replaced by deuterium, in which n is the number of hydrogensin the molecule. Such compounds exhibit increased resistance tometabolism and are thus useful for increasing the half life of anycompound of Formula I when administered to a mammal. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”,Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. An ¹⁸F labeled compound may be useful for PET orSPECT studies. Isotopically labeled compounds of this disclosure andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent. Further, substitutionwith heavier isotopes, particularly deuterium (i.e., ²H or D) may affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements or an improvement in therapeutic index. It is understoodthat deuterium in this context is regarded as a substituent in thecompound of the Formula I, or any formula disclosed herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

The term “treatment” or “treating” refers to the administration of acompound as disclosed herein to a mammal for the purpose of:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. Amines are of general structure N(R³⁰)(R³¹)(R³²),wherein mono-substituted amines have 2 of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines have 1 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen,whereas tri-substituted amines have none of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ and R³² are selectedfrom a variety of substituents such as hydrogen, optionally substitutedalkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl, heterocyclyl and thelike. The above-mentioned amines refer to the compounds wherein eitherone, two or three substituents on the nitrogen are as listed in thename. For example, the term “cycloalkenyl amine” refers tocycloalkenyl-NH₂, wherein “cycloalkenyl” is as defined herein. The term“diheteroarylamine” refers to NH(heteroaryl)₂, wherein “heteroaryl” isas defined herein and so on.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all diluents,solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the manner of administration and the like, which can readilybe determined by one of ordinary skill in the art.

“Coronary diseases” or “cardiovascular diseases” refer to diseases ofthe cardiovasculature arising from any one or more than one of, forexample, heart failure (including congestive heart failure, diastolicheart failure and systolic heart failure), acute heart failure,ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina(including exercise-induced angina, variant angina, stable angina,unstable angina), acute coronary syndrome, diabetes and intermittentclaudication.

“Intermittent claudication” means the pain associated with peripheralartery disease. “Peripheral artery disease” or PAD is a type ofocclusive peripheral vascular disease (PVD). PAD affects the arteriesoutside the heart and brain. The most common symptom of PAD is a painfulcramping in the hips, thighs or calves when walking, climbing stairs orexercising. The pain is called intermittent claudication. When listingthe symptom intermittent claudication, it is intended to include bothPAD and PVD.

Arrhythmia refers to any abnormal heart rate. Bradycardia refers toabnormally slow heart rate whereas tachycardia refers to an abnormallyrapid heart rate. As used herein, the treatment of arrhythmia isintended to include the treatment of supra ventricular tachycardias suchas atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia,atrial tachycardia and the ventricular tachycardias (VT5), includingidiopathic ventricular tachycardia, ventricular fibrillation,pre-excitation syndrome and Torsade de Pointes (TdP).

2. NOMENCLATURE

Names of compounds of the present disclosure are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto). Other compounds or radicals may be named with commonnames, or systematic or non-systematic names. The naming and numberingof the compounds of the disclosure is illustrated with a representativecompound of Formula I:

which is named3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one.

3. COMPOUNDS OF FORMULA I

Accordingly, in typical embodiments the present disclosure providescompounds that function as sodium channel blockers. In typicalembodiments the disclosure relates to compounds of Formula I:

wherein:

-   -   the dotted line represents an optional double bond;    -   Y is —C(R⁵)₂— or —C(O)—;    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CR³ and X²        is N, and the dotted line is a double bond; or    -   X¹ is C(R³)₂ and X² is NR⁴, —O—, —S—, —S(O)— or —S(O)₂₋, or X¹        and X² are both C(R³)₂, and the dotted line is a single bond;        -   provided that:        -   when the dotted line is a single bond and Y is —C(R⁵)₂—;            then both X¹ and X² are C(R³)₂; and        -   when the dotted line is a double bond; Y is —C(O)—;    -   Q is a covalent bond or C₂₋₄ alkynylene;    -   R¹ is C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, heterocyclyl or        heteroaryl;    -   wherein said C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl,        heterocyclyl or heteroaryl are optionally substituted with one,        two or three substituents independently selected from the group        consisting of halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —R⁶, —C₁₋₆ alkylene-R⁶, —C₂₋₆ alkenylene-R⁶, —C₂₋₆        alkynylene-R⁶, -L-R⁶, -L-C₁₋₆ alkylene-R⁶, —C₁₋₆ alkylene-L-R⁶        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁶;    -   L is —O—, —S—, —C(O)—, —S(O)₂, —NR²⁰S(O)₂, —S(O)₂NR²⁰—,        —C(O)NR²⁰— or —NR²⁰C(O)—; provided that when Y is —C(R⁵)₂—, then        L is C(O)— or —S(O)₂—, and R² is -L-R⁶, -L-C₁₋₆ alkylene-R⁶,        —C₁₋₆ alkylene-L-R⁶ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁶;    -   each R³ is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₃₋₆ cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl,                    aryl, heterocyclyl and heteroaryl are optionally                    further substituted with one, two or three                    substituents independently selected from the group                    consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when X¹ is C(R³)₂, two R³ can join together with the with the        carbon atom to which they are attached to form a C₃₋₆ cycloalkyl        or heterocyclyl;    -   R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, —C(O)—OR²⁰,        —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰, C₃₋₆ cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₃₋₆ cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl,                    aryl, heterocyclyl, heteroaryl, are optionally                    further substituted with one, two or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —N(R²⁰)(R²²),                    —C(O)—R²⁰, C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                    —O—R²⁰;    -   each R⁵ is independently hydrogen or C₁₋₆ alkyl;    -   R⁶ is C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₃₋₆ cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂, C₃₋₆            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)— C(O)—R²², C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰, —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —NO₂, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,                —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    C₁₋₆ alkyl, halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²),                    —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN,                    —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently hydrogen, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,        heterocyclyl, aryl or heteroaryl; and        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, aralkyl, —N(R²⁶)(R²⁸),            aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, —C(O)—R²⁶, —C(O)—OR²⁶, aryl, C₃₋₆            cycloalkyl, heterocyclyl, aryl and heteroaryl;            -   wherein said aralkyl, heterocyclyl or heteroaryl is                optionally further substituted with C₁₋₄ alkyl, —CF₃,                aryl or C₃₋₆ cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, heteroaryloxy,        substituted amino, aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃        alkoxy, hydroxymethyl, —CF₃, —OCF₃₅ aryl, heteroaryl and C₃₋₆        cycloalkyl; and    -   R²⁶ and R²⁸ are each independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₃₋₆        cycloalkyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl or heteroaryl            may be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃, —OCF₃ and C₃₋₆            cycloalkyl;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula IA:

wherein the dotted line, Q, Y, R¹, R², X¹ and X² are as defined forFormula I.

In certain embodiments, the compound of Formula I is represented byFormula ID:

wherein Q, Y, R¹, R², X¹ and X² are as defined for Formula I.

In certain embodiments of Formula I or IA, Q is a bond.

In certain embodiments of Formula I or IA, R² is —R⁶, —C₁₋₆ alkylene-R⁶,-L-R⁶, -L-C₁₋₆ alkylene-R⁶, —C₁₋₆ alkylene-L-R⁶ or —C₁₋₆ alkylene-L-C₁₋₆alkylene-R⁶.

In certain embodiments of Formula I or IA, R² is —R⁶, —C₁₋₆ alkylene-R⁶,-L-R⁶, -L-C₁₋₆ alkylene-R⁶ or —C₁₋₆ alkylene-L-R⁶;

-   -   L is —O—, —C(O)—, —S(O)₂—, —S(O)₂NR²⁰— or —C(O)NR²⁰—; provided        that when Y is —C(R⁵)₂—, then L is —C(O)— or —S(O)₂—, and R² is        -L-R⁶, -L-C₁₋₆ alkylene-R⁶ or —C₁₋₆ alkylene-L-R⁶; and    -   R⁶ is C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₃₋₆ cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, halo, C₃₋₆ cycloalkyl, aryl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—OR²⁰, —S(O)₂—R²⁰, —CN and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl or heteroaryl are optionally                further substituted with one, two or three substituents                independently selected from the group consisting of                halo, C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl,                —C(O)—OR²⁰ and —O—R²⁰; and                -   wherein said heteroaryl is optionally further                    substituted with one, two or three C₁₋₆ alkyl.

In certain embodiments of Formula I or IA, R² is

In certain embodiments of Formula I or IA, R¹ is aryl or heteroaryl.

In certain embodiments of Formula I or IA, R¹ is aryl or heteroaryl;

-   -   wherein said aryl or heteroaryl are optionally substituted with        one, two or three substituents independently selected from the        group consisting of halo, —O—R²⁰, C₁₋₄ alkyl, C₃₋₆ cycloalkyl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl or C₃₋₆ cycloalkyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo and            —CN.

In certain embodiments of Formula I or IA, R¹ is aryl or heteroaryloptionally substituted with trifluoromethoxy or trifluoromethyl.

In certain embodiments, the compound of Formula I is represented byFormula II:

wherein Q and R² are as defined in for Formula I;A¹ is aryl or heteroaryl;n is 0, 1, 2 or 3; andR¹⁰ is halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,—C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl, heteroaryl orheterocyclyl; and

-   -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —NO₂, aryl,        heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,        —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and        —O—R²⁰.

In some embodiments of Formula I, IA or II, Q is a bond.

In some embodiments of Formula I, IA or II, R² is —R⁶, —C₁₋₆ alkylene-R⁶or -L-C₁₋₆ alkylene-R⁶;

L is —O—, —C(O)— or —C(O)NR²⁰—;

R⁶ is C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said cycloalkyl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        halo, C₃₋₆ cycloalkyl, aryl, heteroaryl, —C(O)—OR²⁰, —CN and        —O—R²⁰;        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally further            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, and —O—R²⁰;            and            -   wherein said heteroaryl is optionally further                substituted with one, two or three C₁₋₆ alkyl.

In some embodiments of Formula I, IA or II, R² is

In some embodiments of Formula II, R¹⁰ is —O—R²⁰, C₁₋₄ alkyl, C₃₋₆cycloalkyl or heterocyclyl; and

-   -   wherein said C₁₋₄ alkyl or C₃₋₆ cycloalkyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo and —CN.

In some embodiments of Formula II, R¹⁰ is 1-cyanocyclopropyl,2,2,2-trifluoroethoxy, 4-chlorophenoxy, cyclopropyl, phenoxy,piperidin-1-yl, trifluoromethoxy or trifluoromethyl.

In certain embodiments, the compound of Formula I is represented byFormula III:

wherein R² is as defined for Formula I;n is 0, 1, 2 or 3; andR¹⁰ is halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,—C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl, heteroaryl andheterocyclyl; and

-   -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —NO₂, aryl,        heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,        —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and        —O—R²⁰.

In some embodiments of Formula I, IA or III, R² is —C₁₋₆ alkylene-R⁶ or—C₁₋₆ alkylene-L-R⁶;

L is —O—; and

R⁶ is aryl or heteroaryl;

-   -   wherein said heteroaryl is optionally substituted with one, two        or three substituents independently selected from the group        consisting of C₁₋₆ alkyl, halo, C₃₋₆ cycloalkyl, heteroaryl, —CN        and —O—R²⁰.

In some embodiments of Formula I, IA or III, R² is

In some embodiments of Formula III, R¹⁰ is trifluoromethoxy.

In certain embodiments, the compound of Formula I is represented byFormula IV:

wherein R² is as defined for Formula I;n is 0, 1, 2 or 3; andR¹⁰ is halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,—C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl, heteroaryl orheterocyclyl; and

-   -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —NO₂, aryl,        heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,        —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and        —O—R²⁰.

In some embodiments of Formula I, IA or IV, R² is —C₁₋₆ alkylene-R⁶; andR⁶ is heteroaryl;

wherein said heteroaryl is optionally substituted with C₁₋₆ alkyl.

In some embodiments of Formula I, IA or IV, R² is

In some embodiments of Formula IV, R¹⁰ is trifluoromethoxy.

In certain embodiments, the compound of Formula I is represented byFormula V:

wherein R² and R³ are as defined for Formula I;

X² is —O— or —S—;

n is 0, 1, 2 or 3; andR¹⁰ is halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,—C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—S(O)₂—R²², —S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl, heteroaryl orheterocyclyl; and

-   -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —NO₂, aryl,        heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,        —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)— OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and        —O—R²⁰.

In some embodiments of Formula I, IA or V, X² is —O—.

In some embodiments of Formula I, IA or V, X² is —S—.

In some embodiments of Formula I, IA or V, R² is —C₁₋₆ alkylene-R⁶; andR⁶ is aryl or heteroaryl;

wherein said aryl or heteroaryl are optionally substituted with one, twoor three halo.

In some embodiments of Formula I, IA or V, R² is

In some embodiments of Formula I, IA or V, R³ is hydrogen or C₁₋₆ alkyl.

In some embodiments of Formula I, IA or V, R³ is hydrogen or methyl.

In some embodiments of Formula V, R¹⁰ is trifluoromethyl ortrifluoromethoxy.

In certain embodiments, the compound of Formula I is represented byFormula VI:

wherein Q, Y and R² are as defined for Formula I;n is 0, 1, 2 or 3; andR¹⁰ is halo, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,—N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—S(O)₂—R²²,—S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl; and

-   -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆        cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —NO₂, aryl,        heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,        —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and        —O—R²⁰.

In some embodiments of Formula I, IA or III, R² is —C₁₋₆ alkylene-R⁶,-L-R⁶ or -L-C₁₋₆ alkylene-R⁶; provided that when Y is —C(R⁵)₂—, then R²is -L-R⁶ or -L-C₁₋₆ alkylene-R⁶;

L is —C(O)—, —S(O)₂— or —C(O)NR²⁰—;

R⁶ is C₃₋₆ cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said heteroaryl or heterocyclyl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of C₁₋₆ alkyl, halo,        —C(O)—OR²⁰ and —O—R²⁰;        -   wherein said C₁₋₆ alkyl is optionally further substituted            with one, two or three substituents independently selected            from the group consisting of aryl, —N(R²⁰)(R²²), —C(O)—OR²⁰            and —O—R²⁰.

In some embodiments of Formula I, IA or VI, R² is

In some embodiments of Formula VI, each R¹⁰ is independently chloro,fluoro, trifluoromethyl and trifluoromethoxy.

OTHER EMBODIMENTS

Accordingly, in other embodiments, the present disclosure providescompounds that function as sodium channel blockers. In typicalembodiments the disclosure relates to compounds of Formula I:

wherein:

-   -   the dotted line represents an optional double bond;    -   R¹ is selected from the group consisting of cycloalkyl,        cycloalkenyl, aryl and heteroaryl;    -   wherein said cycloalkyl, cycloalkenyl, aryl or heteroaryl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of halo, —NO₂,        CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(O)₂— R²⁰, cycloalkyl, aryl heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂,                    —CF₃₅—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   Q is selected from the group consisting of a covalent bond and        C₂₋₄ alkynylene;    -   Y is selected from the group consisting of —C(R⁵)₂— and —C(O)—;        provided that when    -   Y is —C(R⁵)₂—, then R² is —C(O)—R²⁶, —C(O)—O—R²⁶, or        —C(O)—N(R²⁶)(R²⁸);    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CR³ and X²        is N, and the dotted line is a double bond; or    -   X¹ is C(R³)₂ and X² is NR⁴, X¹ is C(R³)₂ and X² is —O—, or X¹        and X² are both C(R³)₂, and the dotted line is a single bond;    -   each R³ is independently selected from the group consisting of        hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl and heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when X¹ is C(R³)₂, two R³ can join together with the with the        carbon atom to which they are attached to form a cycloalkyl or        heterocyclyl;    -   R⁴ is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   each R⁵ is independently selected from the group consisting of        hydrogen and C₁₋₁₅ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy,        substituted amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy,        —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of formula I is represented byFormula IA:

wherein:

-   -   the dotted line represents an optional double bond;    -   R¹ is selected from the group consisting of cycloalkyl,        cycloalkenyl, aryl and heteroaryl;    -   wherein said cycloalkyl, cycloalkenyl, aryl or heteroaryl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of halo, —NO₂,        CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   Q is selected from the group consisting of a covalent bond and        C₂₋₄ alkynylene;    -   Y is selected from the group consisting of —C(R⁵)₂— and —C(O)—;        provided that when    -   Y is —C(R⁵)₂—, then R² is —C(O)—R²⁶, —C(O)—O—R²⁶, or        —C(O)—N(R²⁶)(R²⁸);    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CR³ and X²        is N, and the dotted line is a double bond; or    -   X¹ is C(R³)₂ and X² is NR⁴, X¹ is C(R³)₂ and X² is —O—, or X¹        and X² are both C(R³)₂, and the dotted line is a single bond;    -   each R³ is independently selected from the group consisting of        hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl and heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when X¹ is C(R³)₂, two R³ can join together with the with the        carbon atom to which they are attached to form a cycloalkyl or        heterocyclyl;    -   R⁴ is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   each R⁵ is independently selected from the group consisting of        hydrogen and C₁₋₁₅ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy,        substituted amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy,        —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula I or IA, R¹ is aryl or heteroaryl;

-   -   wherein said aryl or heteroaryl are optionally substituted with        one, two or three substituents independently selected from the        group consisting of —O—CF₃, —O—R²⁰, C₁₋₄ alkyl, cycloalkyl, and        heterocyclyl; and        -   wherein said alkyl, and cycloalkyl, are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            and —CN; and    -   R²⁰ in each instance is independently C₁₋₁₅ alkyl or aryl;        -   wherein the alkyl or aryl is optionally substituted with            one, two or three halo.

In some embodiments of Formula I or IA, R¹ is selected from the groupconsisting of 6-CF₃-pyridin-3-yl,6-(2,2,2-trifluoroethoxyl)pyridin-3-yl, 4-phenoxy-phenyl, 4-OCF₃-phenyl,4-cyclopropylphenyl, 4-(4-chlorophenoxyl)phenyl,4-(1-cyanocyclopropyl)phenyl and 2-(piperidin-1-yl)pyrimidin-5-yl.

In some embodiments of Formula I or IA, R² is hydrogen, C₁₋₁₅ alkyl,—C(O)—R²⁶, C₁₋₄ alkoxy, cycloalkyl or heterocyclyl;

-   -   wherein said C₁₋₁₅ alkyl, alkoxy, cycloalkyl, and heterocyclyl        are optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        C₁₋₄ alkyl, alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl,        —N(R²⁰)(R²²), —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and        —O—R²⁰;        -   wherein said alkyl, aryl or heteroaryl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, heteroaryl,            cycloalkyl, benzyl, aryl, —CN, and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl and heteroaryl; and        -   wherein the alkyl, and heteroaryl are optionally substituted            with one, two or three substituents independently selected            from the group consisting of halo, —CN, cycloalkyl and            heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of halo, C₁₋₁₅        alkyl, phenyl, —CF₃ and heteroaryl; and

R²⁶ is heteroaryl.

In some embodiments of Formula I or IA, R² is hydrogen, methyl,

In certain embodiments, the compound of formula I is represented byFormula IIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂— R²⁰, cycloalkyl, aryl heteroaryl or        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl,        -   C₁₋₄ alkoxy, C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy,        substituted amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy,        —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula IIA, R² is selected from the groupconsisting of hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl andheterocyclyl. In many embodiments the alkyl, alkoxy, cycloalkyl, andheterocyclyl moiety is further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, alkyl, alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl,—N(R²⁰)(R²²), —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;

-   -   wherein said alkyl or heteroaryl are optionally further        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₄        alkoxy, benzyl, aryl, heteroaryl and cycloalkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl and heteroaryl; and        -   wherein the heteroaryl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of —CN and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of alkyl,        phenyl, —CF₃ and heteroaryl.

Exemplary R² moieties of Formula IIA include, but are not limited to,hydrogen,

In some embodiments of Formula IIA, R¹⁰ is selected from the groupconsisting of —OCF₃, cycloalkyl and —O—R²⁰; and R²⁰ is aryl. In manyembodiments the cycloalkyl is optionally further substituted with —CN.In many embodiments R²⁰ is optionally substituted with halo.

Exemplary R¹⁰ moieties of Formula IIA include, but are not limited to,—OCF₃, cyclopropyl, 1-cyanocyclopropyl, phenoxy and 4-chlorophenoxy.

Exemplary compounds of Formula IIA include

-   6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-chloropyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-phenoxyphenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-phenylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   3-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   3-(2-(pyrimidin-4-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   3-(2-(pyrimidin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-phenyl-1H-tetrazol-1-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   3-((4,5-dimethyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4    (3H)-one;-   3-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   34(5-methylisoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((2H-benzo[d][1,2,3]triazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)acetonitrile;-   3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   1-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)cyclopropanecarbonitrile;-   3-((1-((2-methyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)ethoxy)pyrimidine-4-carbonitrile;-   3-(piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(pyrimidin-2-yl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(morpholinomethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-benzyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-methoxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3    #4,6-dimethoxypyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(but-3-ynyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   1-(4-(4-oxo-3-(2-(pyrimidin-2-yloxy)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)phenyl)cyclopropanecarbonitrile;-   2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)ethoxy)pyrimidine-5-carbonitrile;-   6-(4-(trifluoromethoxy)phenyl)-3-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   methyl    1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropanecarboxylate;-   3-(pyrimidin-2-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((2-ethyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(pyridin-3-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)-3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(3-methoxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   ethyl    4-oxo-3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)piperidine-1-carboxylate;-   6-(4-cyclopropylphenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((pyrimidin-2-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(3-hydroxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2,2-dimethyl-3-(pyrimidin-2-yloxy)propyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((2-methyloxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((4-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-cyclobutyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((2-methyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;    and-   3-(2-cyclopropyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula IIIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy,        substituted amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy,        —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula IIIA, R² is hydrogen or C₁₋₁₅ alkyl. Inmany embodiments the alkyl moiety is further substituted with one, twoor three substituents) independently selected from the group consistingof hydroxyl, aryl, heteroaryl, —N(R²⁰)(R²²), and —O—R²⁰; and

-   -   wherein said aryl, or heteroaryl are optionally further        substituted with one, two or three substituents independently        selected from the group consisting of hydroxyl, halo, C₁₋₄        alkyl, C₁₋₄ alkoxy, heteroaryl, cycloalkyl, —CN, and —O—R²⁰;    -   R²⁰ and R²² in each instance are independently selected from the        group consisting of C₁₋₁₅ alkyl, and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, and heteroaryl are optionally            substituted with halo or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heteroaryl ring which is then optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl, and        heteroaryl.

Exemplary R² moieties of Formula IIIA include, but are not limited to,hydrogen, methyl,

An exemplary R¹⁰ moiety of Formula IIIA includes —OCF₃.

Exemplary compounds of Formula IIIA include

-   7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((3-methyl-1;2;4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((5-methyl-1;2;4-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-methyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-benzyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)benzonitrile;-   2-phenethyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(1H-pyrrol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((4-methyl-1;2;5-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   6-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)pico    linonitrile;-   7-(4-(trifluoromethoxy)phenyl)-2-((5-(3-(trifluoromethyl)phenyl)-1;2;4-oxadiazol-3-yl)methyl)phthalazin-1    (2H)-one;-   2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((4;6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   7-(4-(trifluoromethoxy)p    henyl)-2-((6-(trifluoromethyl)pyridin-2-yl)methyl)phthalazin-1    (2H)-one;-   2-((4;6-dimethylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((4-cyclopropylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(3;5-dimethyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(1H-1;2;4-triazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((4-(cyclopropylmethoxy)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(4-cyclopropylpyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   24(5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(pyrimidin-4-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(5-chloropyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(1H-pyrazol-1-yl)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1    (2H)-one;-   2-(2-(pyrazin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;    and-   2-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula IVA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂— R²⁰, cycloalkyl, aryl heteroaryl or        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   each R³ is independently selected from the group consisting of        hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl and heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, substituted        amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,        aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula IVA, R² is C₁₋₁₅ alkyl. In manyembodiments the alkyl moiety is further substituted with heteroaryl;wherein said heteroaryl is optionally further substituted with C₁₋₆alkyl.

Exemplary R² moieties of Formula IVA include, but are not limited to,

An exemplary R¹⁰ moiety of Formula IVA includes —OCF₃.

Exemplary compounds of Formula IVA include

-   3-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;    and-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula VA:

wherein:

-   -   A is heteroaryl;    -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂— R²⁰, cycloalkyl, aryl heteroaryl or        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)R²⁰, C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, substituted        amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,        aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula VA, A is selected from the groupconsisting of pyridin-3-yl and pyrimidin-5-yl.

In some embodiments of Formula VA, n is 1.

In some embodiments of Formula VA, R² is hydrogen or C₁₋₁₅ alkyl. Inmany embodiments the alkyl moiety is further substituted withheteroaryl; wherein said heteroaryl is optionally further substitutedwith one, two or three substituents independently selected from thegroup consisting of heteroaryl and —O—R²⁰; wherein said heteroaryl isoptionally further substituted with C₁₋₆ alkyl; and R²⁰ is heteroaryl.

Exemplary R² moieties of Formula VA include, but are not limited to,

In some embodiments of Formula VA, R² is —N(R²⁰)(R²²), —O— R²⁰, C₁₋₄alkyl or heteroaryl; wherein R²⁰ and R²² are in each instanceindependently C₁₋₁₅ alkyl, and the C₁₋₁₅ alkyl is optionally substitutedwith one, two or three halo; or R²⁰ and R²² are attached to a commonnitrogen atom R²⁰ and R²² may join to form a heterocyclic ring. In manyembodiments the C₁₋₁₅ alkyl or heteroaryl moiety of R² is furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, and C₁₋₆ alkyl.

Exemplary R¹⁰ moieties of Formula VA include 2,2,2-trifluoroethoxy, —CF₃and piperidin-1-yl.

Exemplary compounds of Formula VA include

-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(6-(2,2,2-trifluoro    ethoxy)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyrimidin-2-yloxy)ethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one;    and-   6-(2-(piperidin-1-yl)pyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula VIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰)—S(═O)₂—N(R²⁰)(R²²), C₁₋₄ alkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(O)₂— R²⁰, cycloalkyl, aryl heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰), (R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   each R³ is independently selected from the group consisting of        hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl and heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, substituted        amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,        aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula VIA, R² is hydrogen.

An exemplary R¹⁰ moiety of Formula VIA includes —OCF₃.

In some embodiments of Formula VIA, R³ is C₁₋₁₅ alkyl. An exemplary R³moiety of Formula VI includes methyl.

An exemplary compound of Formula VIA includes4-methyl-6-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula VIIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂— R²⁰, cycloalkyl, aryl heteroaryl or        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —(C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, substituted        amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,        aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula VIIA, R² is C₁₋₁₅ alkyl. In manyembodiments the alkyl moiety is further substituted with —O—R²⁰; whereinR²⁰ is heteroaryl.

An exemplary R² moiety of Formula VIIA includes

An exemplary R¹⁰ moiety of Formula VIIA includes —OCF₃.

An exemplary compound of Formula VIIA includes3-(2-(pyrimidin-2-yloxy)ethyl)-6-((4-(trifluoromethoxy)phenyl)ethynyl)benzo[d][1,2,3]triazin-4(3H)-one;

-   -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula VIIIA:

wherein:

-   -   n is 1, 2 or 3:    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₅        alkyl, C₁₋₄ alkoxy, —C(O)—R²⁶, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸),        —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl aryl,            heteroaryl or heterocyclyl are optionally substituted with            one, two or three substituents independently selected from            the group consisting of hydroxyl, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,            C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, aralkyl,                    cycloalkyl, aryl, heterocyclyl or heteroaryl, are                    optionally further substituted with one, two or                    three substituents independently selected from the                    group consisting of hydroxyl, halo, —NO₂, —CF₃,                    —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   each R³ is independently selected from the group consisting of        hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl and                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl and heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ can join together with the with the carbon atom to        which they are attached to form a cycloalkyl or heterocyclyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, substituted        amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,        aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula VIIA, R² is C₁₋₁₅ alkyl;

-   -   wherein said alkyl is optionally substituted with heteroaryl;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

Exemplary R² moieties of Formula VIIA include

Exemplary R¹⁰ moieties of Formula VIIA include hydrogen, —CF₃ and —OCF₃.

Exemplary compounds of Formula VIIIA include

-   3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one;-   3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one;-   2-methyl-3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one;    and-   2,2-dimethyl-3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In certain embodiments, the compound of Formula I is represented byFormula IXA:

wherein:

-   -   n is 1, 2 or 3:    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl        and heterocyclyl; and        -   wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is selected from the group consisting of —C(O)—R²⁶,        —C(O)—OR²⁶ and —C(O)—N(R²⁶)(R²⁸);    -   Q is selected from the group consisting of a covalent bond and        C₂₋₄ alkynylene;    -   Y is selected from the group consisting of —C(R⁵)₂— and —C(O);    -   each R⁵ is independently selected from the group consisting of        hydrogen and C₁₋₁₅ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, substituted amino, aminoacyl,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy,        substituted amino, aminoacyl, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy,        —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl and        heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, cycloalkyl, aryl or heteroaryl may            be further substituted with from 1 to 3 substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

In some embodiments of Formula IXA, R² is C₁₋₁₅ alkyl;

-   -   wherein said alkyl is optionally substituted with heteroaryl;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, tautomer, polymorph and/or prodrug thereof.

Exemplary R² moieties of Formula IXA include

Exemplary R¹⁰ moieties of Formula IXA include hydrogen, —CF₃ and —OCF₃.

Exemplary compounds of Formula IXA include

-   2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;-   2-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;-   2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one;-   2-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one;-   2-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one;-   pyridin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;    or-   pyrimidin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, tautomer, polymorph and/or prodrug thereof.

In one embodiment, at least one of the substituents (i.e., at least oneof R¹, R², R³ is not hydrogen.

In other embodiments, the present disclosure provides compounds ofFormula IB:

wherein:

-   -   the dotted line represents an optional double bond;    -   R¹ is aryl or heteroaryl;    -   wherein said aryl or heteroaryl are optionally substituted with        one, two, or three substituents independently selected from the        group consisting of halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃,        —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)OH, —N(R²⁰)(R²²), —C(O)—N        (R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰,        —S(═O)₂, —N(R²⁰)(R²²), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl, and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —NO₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   Q is a covalent bond or C₂₋₄ alkynylene;    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CH₂ and X²        is NR⁴;    -   R³ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl is optionally substituted with one, two,            or three substituents independently selected from the group            consisting of halo, —NO₂, aryl, heterocyclyl, heteroaryl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), CN, and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl, or                heteroaryl are optionally further substituted with one,                two, or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, benzyl,                aryl, heterocyclyl, heteroaryl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, benzyl, aryl, heterocyclyl,                    heteroaryl, cycloalkyl, are optionally further                    substituted with one, two, or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;    -   R⁴ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl is optionally substituted with one, two,            or three substituents independently selected from the group            consisting of halo, —NO₂, aryl, heterocyclyl, heteroaryl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), CN, and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl, or                heteroaryl are optionally further substituted with one,                two, or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, benzyl,                aryl, heterocyclyl, heteroaryl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, benzyl, aryl, heterocyclyl,                    heteroaryl, cycloalkyl, are optionally further                    substituted with one, two, or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), CN, and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl;    -   R²⁵ is in each instance independently a covalent bond or C₁-C₃        alkylene optionally substituted with one or two C₁-C₃ alkyl        groups; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In certain embodiments, the compound of formula IB is represented byFormula IC:

wherein:

-   -   the dotted line represents an optional double bond;    -   R¹ is aryl or heteroaryl;        -   wherein said aryl or heteroaryl are optionally substituted            with one, two, or three substituents independently selected            from the group consisting of halo, —NO₂, CN, —SF₅,            —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, C(O)OH,            —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,            —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄            alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl,            heteroaryl, and heterocyclyl; and wherein said alkyl,            alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or            heterocyclyl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —NO₂,            —O—CF₃₅—O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   Q is a covalent bond or C₂₋₄ alkynylene;    -   X¹ is N and X² is N, X¹ is N and X² is CR³, or X¹ is CH₂ and X²        is NR⁴;    -   R³ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl is optionally substituted with one, two,            or three substituents independently selected from the group            consisting of halo, —NO₂, aryl, heterocyclyl, heteroaryl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl, or                heteroaryl are optionally further substituted with one,                two, or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, benzyl,                aryl, heterocyclyl, heteroaryl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, benzyl, aryl, heterocyclyl,                    heteroaryl, cycloalkyl, are optionally further                    substituted with one, two, or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;    -   R⁴ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl is optionally substituted with one, two,            or three substituents independently selected from the group            consisting of halo, —NO₂, aryl, heterocyclyl, heteroaryl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl, or                heteroaryl are optionally further substituted with one,                two, or three substituents independently selected from                the group consisting of hydroxyl, halo, —NO₂, C₁₋₆                alkyl, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, benzyl, aryl, heterocyclyl,                    heteroaryl, cycloalkyl, are optionally further                    substituted with one, two, or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl;    -   R²⁵ is in each instance independently a covalent bond or C₁-C₃        alkylene optionally substituted with one or two C₁-C₃ alkyl        groups; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula IB or IC, R¹ is aryl or heteroaryl;

-   -   wherein said aryl or heteroaryl are optionally substituted with        one, two, or three substituents independently selected from the        group consisting of —O—CF₃, —O—R²⁰, C₁₋₄ alkyl, cycloalkyl, and        heterocyclyl; and        -   wherein said alkyl, and cycloalkyl, are optionally            substituted with one, two, or three substituents            independently selected from the group consisting of halo,            and —CN; and    -   R²⁰ in each instance is independently C₁-C₁₅ alkyl or aryl;        -   wherein the alkyl or aryl is optionally substituted with            one, two, or three halo.

In some embodiments of Formula IB or IC, R¹ is selected from the groupconsisting of 6-CF₃-pyridin-3-yl,6-(2,2,2-trifluoroethoxyl)pyridin-3-yl, 4-phenoxy-phenyl,

-   4-OCF₃-phenyl, 4-cyclopropylphenyl, 4-(4-chlorophenoxyl)phenyl,-   4-(1-cyanocyclopropyl)phenyl, and 2-(piperidin-1-yl)pyrimidin-5-yl.

In some embodiments of Formula IB or IC, R² is hydrogen, C₁₋₁₅ alkyl,C₁₋₄ alkoxy, cycloalkyl, or heterocyclyl;

-   -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are        optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        alkyl, alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl,        —N(R²⁰)(R²²), —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo, and        —O—R²⁰;        -   wherein said alkyl, aryl or heteroaryl are optionally            further substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, heteroaryl,            cycloalkyl, benzyl, aryl, —CN, and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, and heteroaryl; and        -   wherein the alkyl, and heteroaryl are optionally substituted            with one, two, or three substituents independently selected            from the group consisting of halo, —CN, cycloalkyl and            heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of halo, alkyl,        phenyl, —CF₃, and heteroaryl.

In some embodiments of Formula IB or IC, R² is hydrogen, methyl,

In certain embodiments, the compound of formula IB is represented byFormula IIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—) N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —NO₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula IIA, R² is selected from the groupconsisting of hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, cycloalkyl, andheterocyclyl. In many embodiments the alkyl, alkoxy, cycloalkyl, andheterocyclyl moiety is further substituted with one, two, or threesubstituents independently selected from the group consisting ofhydroxyl, alkyl, alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl,—N(R²⁰)(R²²), —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo, and —O—R²⁰;

-   -   wherein said alkyl or heteroaryl are optionally further        substituted with one, two, or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₄        alkoxy, benzyl, aryl, heteroaryl and cycloalkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, and heteroaryl; and    -   wherein the heteroaryl is optionally substituted with one, two,        or three substituents independently selected from the group        consisting of —CN and heteroaryl;        -   wherein said heteroaryl is optionally further substituted            with cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of alkyl,        phenyl, —CF₃, and heteroaryl.

Exemplary R² moieties of Formula IIA include, but are not limited to,hydrogen,

In some embodiments of Formula IIA, R¹⁰ is selected from the groupconsisting of —OCF₃, cycloalkyl, and —O—R²⁰; and R²⁰ is aryl. In manyembodiments the cycloalkyl is optionally further substituted with —CN.In many embodiments R²⁰ is optionally substituted with halo.

Exemplary R¹⁰ moieties of Formula IIA include, but are not limited to,—OCF₃, cyclopropyl, 1-cyanocyclopropyl, phenoxy and 4-chlorophenoxy.

Exemplary compounds of Formula IIA include

-   6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(5-chloropyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-phenoxyphenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-phenylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyrimidin-4-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyrimidin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-phenyl-1H-tetrazol-1-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((4,5-dimethyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-methylisoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((2H-benzo[d][1,2,3]triazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetonitrile;-   3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   1-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)cyclopropanecarbonitrile;-   3-((1-((2-methyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3    (4H)-yl)ethoxy)pyrimidine-4-carbonitrile;-   3-(piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(pyrimidin-2-yl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(morpholinomethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-benzyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-methoxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((4,6-dimethoxypyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(but-3-ynyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   1-(4-(4-oxo-3-(2-(pyrimidin-2-yloxy)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)phenyl)cyclopropanecarbonitrile;-   2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)ethoxy)pyrimidine-5-carbonitrile;-   6-(4-(trifluoromethoxy)phenyl)-3-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   methyl    1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropanecarboxylate;-   3-(pyrimidin-2-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((2-ethyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(pyridin-3-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   6-(4-(4-chlorophenoxyl)phenyl)-3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(3-methoxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   ethyl    4-oxo-3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine-1-carboxylate;-   6-(4-cyclopropylphenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-((1-((pyrimidin-2-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(3-hydroxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;    and-   3-(2,2-dimethyl-3-(pyrimidin-2-yloxy)propyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    polymorph, and/or prodrug thereof.

In certain embodiments, the compound of Formula IB is represented byFormula IIIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂— R²⁰, —S(═O)₂—) N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —NO₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²)CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)                    —N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula IIIA, R² is hydrogen or C₁₋₁₅ alkyl. Inmany embodiments the alkyl moiety is further substituted with one, two,or three substituents) independently selected from the group consistingof hydroxyl, aryl, heteroaryl, —N(R²⁰)(R²²), and —O—R²⁰; and

-   -   wherein said aryl, or heteroaryl are optionally further        substituted with one, two, or three substituents independently        selected from the group consisting of hydroxyl, halo, C₁₋₆        alkyl, C₁₋₄ alkoxy, heteroaryl, cycloalkyl, —CN, and —O—R²⁰;    -   R²⁰ and R²² in each instance are independently selected from the        group consisting of C₁-C₁₅ alkyl, and heteroaryl; and        -   wherein the alkyl, and heteroaryl are optionally substituted            with halo or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heteroaryl ring which is then optionally        substituted with one, two, or three substituents independently        selected from the group consisting of halo, alkyl, and        heteroaryl.

Exemplary R² moieties of Formula IIIA include, but are not limited to,hydrogen, methyl,

An exemplary R¹⁰ moiety of Formula IIIA includes —OCF₃.

Exemplary compounds of Formula IIIA include

-   7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((3-methyl-1;2;4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((5-methyl-1;2;4-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-methyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-benzyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((l-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)benzonitrile;-   2-phenethyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1H-pyrrol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((4-methyl-1;2;5-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   6-((l-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)picolinonitrile;-   7-(4-(trifluoromethoxy)phenyl)-2-((5-(3-(trifluoromethyl)phenyl)-1;2;4-oxadiazol-3-yl)methyl)phthalazin-1(2H)-one;-   2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((4;6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   7-(4-(trifluoromethoxy)phenyl)-2-((6-(trifluoromethyl)pyridin-2-yl)methyl)phthalazin-1(2H)-one;-   2-((4;6-dimethylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((4-cyclopropylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(3;5-dimethyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1H-1;2;4-triazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2((4-(cyclopropylmethoxy)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(4-cyclopropylpyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   24(5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(pyrimidin-4-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(5-chloropyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(1H-pyrazol-1-yl)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(pyrazin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;-   2-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;    and-   2-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    polymorph, and/or prodrug thereof.

In certain embodiments, the compound of Formula IB is represented byFormula IVB:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂— R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —NO₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²)CN, and O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, C—(O)—O—R²⁰, —C(O)                    —N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula IVB, R² is C₁₋₁₅ alkyl. In manyembodiments the alkyl moiety is further substituted with heteroaryl;wherein said heteroaryl is optionally further substituted with C₁₋₆alkyl.

Exemplary R² moieties of Formula IVB include, but are not limited to,

An exemplary R¹⁰ moiety of Formula IVB includes —OCF₃.

Exemplary compounds of Formula IVB include

-   3-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;-   3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;    and-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    polymorph, and/or prodrug thereof.

In certain embodiments, the compound of Formula IB is represented byFormula VA:

wherein:

-   -   A is heteroaryl;    -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂— R²⁰, —S(═O)₂—) N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —O₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —(R²⁰)(R²²), —CF₃, —C(O)—R²⁰, —C(O)—O—R²⁰,            —C(O)—N(R²⁰)(R²²), —N, oxo, and —O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —O—CF₃, C₁₋₆ alkyl, C₁₋₄ alkoxy,                benzyl, aryl, heterocyclyl, heteroaryl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),                —N, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula VA, A is selected from the groupconsisting of pyridin-3-yl and pyrimidin-5-yl.

In some embodiments of Formula VA, n is 1.

In some embodiments of Formula VA, R² is hydrogen or C₁₋₁₅ alkyl. Inmany embodiments the alkyl moiety is further substituted withheteroaryl; wherein said heteroaryl is optionally further substitutedwith one, two, or three substituents independently selected from thegroup consisting of heteroaryl and —O—R²⁰; wherein said heteroaryl isoptionally further substituted with C₁₋₆ alkyl; and R²⁰ is heteroaryl.

Exemplary R² moieties of Formula VA include, but are not limited to,

In some embodiments of Formula VA, R² is —N(R²⁰)(R²²), —O—R²⁰, C₁₋₄alkyl or heteroaryl; wherein R²⁰ and R²² are in each instanceindependently C₁-C₁₅ alkyl, and the alkyl is optionally substituted withone, two, or three halo; or R²⁰ and R²² are attached to a commonnitrogen atom R²⁰ and R²² may join to form a heterocyclic ring. In manyembodiments the alkyl or heteroaryl moiety of R² is further substitutedwith one, two, or three substituents independently selected from thegroup consisting of halo, and alkyl.

Exemplary R¹⁰ moieties of Formula VA include 2,2,2-trifluoroethoxy,—CF₃, and piperidin-1-yl.

Exemplary compounds of Formula VA include

-   3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(6-(2,2,2-trifluoro    ethoxy)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one;-   3-(2-(pyrimidin-2-yloxy)ethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one;    and-   6-(2-(piperidin-1-yl)pyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    polymorph, and/or prodrug thereof.

In certain embodiments, the compound of Formula IA is represented byFormula VIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂— R²⁰, —S(═O)₂—) N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —O₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            —(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN,            oxo, and O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²), —N, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R³ is hydrogen, C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl, or        heterocyclyl;        -   wherein said alkyl is optionally substituted with one, two,            or three substituents independently selected from the group            consisting of hydroxyl, alkoxy, halo, —NO₂, —O—CF₃, —O—CHF₂,            aryl, heterocyclyl, heteroaryl, cycloalkyl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;            -   wherein said alkoxy, cycloalkyl, aryl, heterocyclyl, or                heteroaryl are optionally further substituted with one,                two, or three substituents independently selected from                the group consisting of hydroxyl, halo, —NO₂, —O—CF₃,                C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl, heterocyclyl,                heteroaryl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰,                —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula VIA, R² is hydrogen.

An exemplary R¹⁰ moiety of Formula VIA includes —OCF₃.

In some embodiments of Formula VIA, R³ is C₁₋₁₅ alkyl. An exemplary R³moiety of Formula VI includes methyl.

An exemplary compound of Formula VIA includes4-methyl-6-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one;

or a pharmaceutically acceptable salt, ester, hydrate, solvate,polymorph, and/or prodrug thereof.

In certain embodiments, the compound of Formula IB is represented byFormula VIIA:

wherein:

-   -   n is 0, 1, 2, or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂— R²⁰, —S(═O)₂—) N(R²⁰)(R²²), C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,        and heterocyclyl; and        -   wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,            cycloalkyl, or heterocyclyl are optionally substituted with            one, two, or three substituents independently selected from            the group consisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl,            heterocyclyl, heteroaryl, C₁₋₄ alkyl, cycloalkyl,            —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²),            —CN, and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl, or heterocyclyl;        -   wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are            optionally substituted with one, two, or three substituents            independently selected from the group consisting of            hydroxyl, alkyl, alkoxy, alkynyl, halo, —O₂, —O—CF₃,            —O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl,            (R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN,            oxo, and O—R²⁰;            -   wherein said alkyl, alkoxy, cycloalkyl, aryl,                heterocyclyl, or heteroaryl are optionally further                substituted with one, two, or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄                alkoxy, benzyl, aryl, heterocyclyl, heteroaryl,                cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl,                    heterocyclyl, heteroaryl, cycloalkyl, are optionally                    further substituted with one, two, or three                    substituents independently selected from the group                    consisting of hydroxyl, halo, —NO₂, —O—CF₃, —CF₃,                    —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,                    —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl,        C₂-C₁₅ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;        and        -   wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and            heteroaryl are optionally substituted with one, two, or            three substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, monoalkylamino,            dialkylamino, alkyl amide, aryl amide, heteroaryl amide,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,            —C(O)—NH₂, —C(O)—NH₂, aryl, cycloalkyl, and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl, or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two, or three substituents        independently selected from the group consisting of hydroxyl,        halo, alkyl, benzyl, phenyl, phenoxy, benzyloxy, monoalkylamino,        dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, alkyl, and cycloalkyl; and        -   wherein the alkyl, phenyl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃, and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

In some embodiments of Formula VIIA, R² is C₁₋₁₅ alkyl. In manyembodiments the alkyl moiety is further substituted with —O—R²⁰; whereinR²⁰ is heteroaryl.

An exemplary R² moiety of Formula VIIA includes

An exemplary R¹⁰ moiety of Formula VIIA includes —OCF₃.

An exemplary compound of Formula VIIA includes3-(2-(pyrimidin-2-yloxy)ethyl)-6-((4-(trifluoromethoxy)phenyl)ethynyl)benzo[d][1,2,3]triazin-4(3H)-one;

-   -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        polymorph, and/or prodrug thereof.

4. FURTHER EMBODIMENTS

In some embodiments, the compounds provided by the present disclosureare effective in the treatment of conditions or diseases known torespond to administration of late sodium channel blockers, including butnot limited to cardiovascular diseases such as atrial and ventriculararrhythmias, including atrial fibrillation, Prinzmetal's (variant)angina, stable angina, unstable angina, ischemia and reperfusion injuryin cardiac, kidney, liver and the brain, exercise induced angina,pulmonary hypertension, congestive heart disease including diastolic andsystolic heart failure, and myocardial infarction. In some embodiments,compounds provided by the present disclosure which function as latesodium channel blockers may be used in the treatment of diseasesaffecting the neuromuscular system resulting in pain, itching, seizures,or paralysis, or in the treatment of diabetes or reduced insulinsensitivity, and disease states related to diabetes, such as diabeticperipheral neuropathy.

Certain compounds of the disclosure may also possess a sufficientactivity in modulating neuronal sodium channels, i.e., Na_(v) 1.1., 1.2,1.5, 1.7, and/or 1.8, and may have appropriate pharmacokineticproperties such that they may active with regard to the central and/orperipheral nervous system. Consequently, some compounds of thedisclosure may also be of use in the treatment of epilepsy or pain oritching of a neuropathic origin.

In one embodiment, this disclosure provides a method of treating adisease state in a mammal that is alleviable by treatment with an agentcapable of reducing late sodium current, comprising administering to amammal in need thereof a therapeutically effective dose of a compound ofFormula I as described above. In another embodiment, the disease stateis a cardiovascular disease selected from one or more of atrial andventricular arrhythmias, heart failure (including congestive heartfailure, diastolic heart failure, systolic heart failure, acute heartfailure), Prinzmetal's (variant) angina, stable and unstable angina,exercise induced angina, congestive heart disease, ischemia, recurrentischemia, reperfusion injury, myocardial infarction, acute coronarysyndrome, peripheral arterial disease, pulmonary hypertension, andintermittent claudication. In another embodiment, the disease state isdiabetes or diabetic peripheral neuropathy. In a further embodiment, thedisease state results in one or more of neuropathic pain, epilepsy,seizures, or paralysis.

In one embodiment, this disclosure provides a method of treatingdiabetes in a mammal, comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of Formula I asdescribed above. Diabetes mellitus is a disease characterized byhyperglycemia; altered metabolism of lipids, carbohydrates and proteins;and an increased risk of complications from vascular disease. Diabetesis an increasing public health problem, as it is associated with bothincreasing age and obesity.

There are two major types of diabetes mellitus: 1) Type I, also known asinsulin dependent diabetes (IDDM) and 2) Type II, also known as insulinindependent or non-insulin dependent diabetes (NIDDM). Both types ofdiabetes mellitus are due to insufficient amounts of circulating insulinand a decrease in the response of peripheral tissue to insulin.

Type I diabetes results from the body's failure to produce insulin, thehormone that “unlocks” the cells of the body, allowing glucose to enterand fuel them. The complications of Type I diabetes include heartdisease and stroke; retinopathy (eye disease); kidney disease(nephropathy); neuropathy (nerve damage); as well as maintenance of goodskin, foot and oral health.

Type II diabetes results from the body's inability to either produceenough insulin or the cells inability to use the insulin that isnaturally produced by the body. The condition where the body is not ableto optimally use insulin is called insulin resistance. Type II diabetesis often accompanied by high blood pressure and this may contribute toheart disease. In patients with type II diabetes mellitus, stress,infection, and medications (such as corticosteroids) can also lead toseverely elevated blood sugar levels. Accompanied by dehydration, severeblood sugar elevation in patients with type II diabetes can lead to anincrease in blood osmolality (hyperosmolar state). This condition canlead to coma.

It has been suggested that ranolazine (RANEXA®, a selective inhibitor ofINaL) may be an antidiabetic agent that causes β-cell preservation andenhances insulin secretion in a glucose-dependent manner in diabeticmice (see, Y. Ning et al. J Pharmacol Exp Ther. 2011, 337(1), 50-8).Therefore it is contemplated that the compounds of Formula I asdisclosed herein can be used as antidiabetic agents for the treatment ofdiabetes.

Pharmaceutical Compositions and Administration

Compounds provided in accordance with the present disclosure are usuallyadministered in the form of pharmaceutical compositions. This disclosuretherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present disclosure in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. Preferably, for parenteral administration, sterileinjectable solutions are prepared containing a therapeutically effectiveamount, e.g., 0.1 to 700 mg, of a compound described herein. It will beunderstood, however, that the amount of the compound actuallyadministered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present disclosure incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g, or alternatively, or 100 mg to 500 mg, of a compounddescribed herein, and for parenteral administration, preferably from 0.1mg to 700 mg, or alternatively, 0.1 mg to 100 mg, of a compound acompound described herein. It will be understood, however, that theamount of the compound actually administered usually will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound administered and its relative activity, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present disclosure may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

Combination Therapy

Patients being treated by administration of the late sodium channelblockers of the disclosure often exhibit diseases or conditions thatbenefit from treatment with other therapeutic agents. These diseases orconditions can be of the cardiovascular nature or can be related topulmonary disorders, metabolic disorders, gastrointestinal disorders andthe like. Additionally, some coronary patients being treated byadministration of the late sodium channel blockers of the disclosureexhibit conditions that can benefit from treatment with therapeuticagents that are antibiotics, analgesics, and/or antidepressants andanti-anxiety agents.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the late sodium channel blockers of thedisclosure with other therapeutic agents include, without limitation,angina including stable angina, unstable angina (UA), exercised-inducedangina, variant angina, arrhythmias, intermittent claudication,myocardial infarction including non-STE myocardial infarction (NSTEMI),pulmonary hypertension including pulmonary arterial hypertension, heartfailure including congestive (or chronic) heart failure and diastolicheart failure and heart failure with preserved ejection fraction(diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the late sodium channel blockers of thedisclosure with therapeutic agents suitable for treating cardiovascularrelated conditions allows enhancement in the standard of care therapythe patient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral®),atenolol (Tenormin®), betaxolol (Kerlone®),bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol(Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®),metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol(Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc®, Lotrel®),bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine(Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®),nisoldipine (Sular®), verapamil (Calm®, Isoptin®, Verelan®), andnicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®),spironolactone (Aldactone®), and eplerenone (Inspra®).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin®),captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®),lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril(Aceon®), quinapril (Accupril®), ramipril (Altace®), andtrandolapril)(Mavik®.

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantinesulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/lllainhibitors, such as abciximab, tirofiban, and eptifibatide(Integrelin®). Beta blockers and calcium channel blockers also have aplatelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interest(see U.S. Patent Application Publication No. 2010/0056536 and U.S.Patent Application Publication No. 2011/0183990, the entirety of whichare incorporated herein).

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot formation.Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress®), doxazosin mesylate(Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide(Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergicantagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol(Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride(Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®,Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride(Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide(Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne®),Trandate®, carvedilol (Coreg®); adrenergic neuron blocking agents, suchas guanethidine (Ismelin®), reserpine (Serpasil®); central nervoussystem-acting antihypertensives, such as clonidine (Catapres®),methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin IIagents; ACE inhibitors, such as perindopril (Aceon®) captopril(Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®);angiotensin-II receptor antagonists, such as candesartan (Atacand®),eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®),telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers,such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine(Adalat®, Procardia®); diuretics; direct vasodilators, such asnitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine(Apresoline®), minoxidil (Loniten®), verapamil; and potassium channelactivators, such as aprikalim, bimakalim, cromakalim, emakalim,nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip®), ciprofibrate)(Modalim®), and statins,such as atorvastatin)(Lipitor®), fluvastatin (Lescol®), lovastatin(Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®)pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin(Zocor®).

In this invention, the patient presenting with an acute coronary diseaseevent often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient a compound as disclosed herein (e.g., Formula I) incombination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol(Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline,ipratropium bromide (Atrovent®), tiotropium (Spiriva®),methylprednisolone (Solu-Medrol®, Medrol®), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix®),lansoprazole (Prevacid®), esomeprazole (Nexium®), omeprazole(Prilosec®), rabeprazole; H2 blockers, such as cimetidine (Tagamet®),ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®);prostaglandins, such as misoprostol (Cytotec®); sucralfate; andantacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with a compound as disclosed herein (e.g., FormulaI).

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include 13-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef®), cephalexin (Keflex®), cephradine (Velosef®), cefaclor(Ceclor®), cefuroxime axtel (Ceftin®), cefprozil (Cefzil®), loracarbef(Lorabid®), cefixime (Suprax®), cefpodoxime proxetil (Vantin®),ceftibuten (Cedax®), cefdinir (Omnicef®), ceftriaxone (Rocephin®),carbapenems, and monobactams; tetracyclines, such as tetracycline;macrolide antibiotics, such as erythromycin; aminoglycosides, such asgentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin;cyclic peptides, such as vancomycin, streptogramins, polymyxins;lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; andsulfa antibiotics, such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the late sodium channel blockers of the disclosure totreat neuropathic pain via inhibition of the Na_(v) 1.7 and 1.8 sodiumchannels, combination with analgesics are particularly envisioned. SeeU.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillers. Examples of antidepressant and anti-anxiety agents includebenzodiazepines, such as diazepam, lorazepam, and midazolam;enzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®,Gladem®, Serlift®, Stimuloton®); escitalopram (Lexapro®, Cipralex®);fluoxetine (Prozac®, Sarafem®, Fluctin®, Fontex®, Prodep®, Fludep®,Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®,Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®);trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion(Wellbutrin®, Zyban®).

Accordingly, one aspect of the disclosure provides for a compositioncomprising the late sodium channel blockers of the disclosure and atleast one therapeutic agent. In an alternative embodiment, thecomposition comprises the late sodium channel blockers of the disclosureand at least two therapeutic agents. In further alternative embodiments,the composition comprises the late sodium channel blockers of thedisclosure and at least three therapeutic agents, the late sodiumchannel blockers of the disclosure and at least four therapeutic agents,or the late sodium channel blockers of the disclosure and at least fivetherapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the late sodium channel blockers of thedisclosure and therapeutic agent or agents, essentially contemporaneousadministration of more than one formulation comprising the late sodiumchannel blocker of the disclosure and therapeutic agent or agents, andconsecutive administration of a late sodium channel blocker of thedisclosure and therapeutic agent or agents, in any order, whereinpreferably there is a time period where the late sodium channel blockerof the disclosure and therapeutic agent or agents simultaneously exerttheir therapeutic affect.

5. SYNTHESIS OF EXAMPLE COMPOUNDS

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula I,may be accomplished as described in the following examples. Ifavailable, reagents may be purchased commercially, e.g. from SigmaAldrich or other chemical suppliers.

General Syntheses

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present invention, inspection of the structure of the compound to besynthesized will provide the identity of each substituent group in viewof the general schemes provided herein. The identity of the finalproduct will generally render apparent the identity of the necessarystarting materials by a simple process of inspection, given the examplesherein.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures, orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989),Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I are typically prepared by first providing themolecular core 1-2; which may be commercially obtained, for example7-bromophthalazin-1(2H)-one, 6-bromophthalazin-1(2H)-one, and the like,or synthesized de novo, and then attaching the desired -Q-R¹substituents using suitable coupling conditions (e.g., Suzuki coupling)and the desired —R² substituents using suitable substitution conditions.These processes are shown below in Scheme 1 for the synthesis of acompound of Formula I (or a compound of Formula IA, IB, IC, ID, II, IIA,III, IIIA, IV, IVA, IVB, V, VA, VI, VIA, VIIA, VIIIA, or IXA).

In general, a halogenated compound of formula 1-1, in this case abrominated compound, is reacted with an appropriately substitutedboronic acid derivative of formula R¹Q-B(OH)₂, or a boronic esterthereof, in an inert solvent, for example aqueous N,N-dimethylformamide,in the presence of a mild base, for example potassium carbonate orsodium bicarbonate. The reaction is typically conducted in the presenceof a metal catalyst with an appropriate ligand, for exampledichlorobis(triphenylphosphine) palladium(II), at a temperature of about120-170° C., for about 10 minutes to about 1 hour or at a lowertemperature, i.e., 90-110° C. for 2 to 5 days. When the reaction issubstantially complete, the product of Formula I is isolated byconventional means.

It will be appreciated that the R² substitutent can be modified or addedeither before (as shown in Scheme 1) or after the addition of the R¹moiety. The R² moiety may be coupled to the core 1-2 under substitutionreaction conditions with an appropriate reagent of formula LG-R² (whereLG is a leaving group such as a halo, hydroxyl, alkoxy, and the like) asshown in Scheme 1. Typical substitution reaction conditions include thepresence of a base, such as potassium carbonate, sodium bicarbonate,triethylamine, and the like, in a polar aprotic solvent, such asN,N-dimethylformamide, and optionally an elevated temperature of about100-150° C., or in a microwave. Also, in the case where the R²substituent contains a heteroaryl ring, the heteroaryl ring may besynthesized and cyclized before or after addition of the -Q-R¹ portion.

Optional Core Synthesis

In certain embodiments, the core may be synthesized and cyclized beforeor after addition of the -Q-R¹ subsitutent (Scheme 2). For example, suchalternative routes for the synthesis of benzo[d][1,2,3]triazin-4(3H)-onecompounds of Formula 2-8 (i.e., Formula II, HA, VA, and VIIA) are shownin Scheme 2, below.

In one embodiment, compounds of Formula 2-2 are prepared fromcommercially available compounds of Formula 2-1 usingbis(trichloromethyl) carbonate. Reaction of compounds of Formula 2-2with ammonia in a suitable solvent, such as THF affords compounds ofFormula 2-3, which are converted to compounds of Formula 2-4 with sodiumnitrite in the presence of an acid, such as hydrochloric acid, in asuitable solvent system, such as aqueous dioxane. Compounds of Formula2-5 can be provided from compounds of Formula 2-4 via reaction with anappropriately substituted boronic acid derivative of formula R¹Q-B(OH)₂,or a boronic ester thereof, under typical coupling reaction conditions.

Typical coupling reaction conditions an inert solvent, for exampleaqueous N,N-dimethylformamide, in the presence of a mild base, forexample potassium carbonate or sodium bicarbonate. The reaction istypically conducted in the presence of a metal catalyst with anappropriate ligand, for example dichlorobis(triphenylphosphine)palladium(II), at a temperature of about 120-170° C., for about 10minutes to about 1 hour or at a lower temperature, i.e., 90-110° C. for2 to 5 days. When the reaction is substantially complete, the compoundsof Formula 2-5 can be isolated by conventional means.

In another embodiment, compounds of Formula 2-5 can be provided fromcompounds of Formula 2-6. For example, compounds of Formula 2-6 arecoupled with an appropriately substituted boronic acid derivative offormula R¹Q-B(OH)₂, or a boronic ester thereof, under typical couplingreaction conditions as described hereinabove, to afford compounds ofFormula 2-7. Compounds of Formula 2-7 are cyclized to afford compoundsof Formula 2-5 using sodium nitrite in the presence of an acid, such ashydrochloric acid, in a suitable solvent system, such as aqueousdioxane.

The R² moiety may be coupled to compounds of Formula 2-5 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy, orthe like) as shown in Scheme 1 to affordbenzo[d][1,2,3]triazin-4(3H)-one compounds of Formula 2-8. Typicalsubstitution reaction conditions include the presence of a base, such aspotassium carbonate, sodium bicarbonate, triethylamine, and the like, ina polar aprotic solvent, such as N,N-dimethylformamide, and optionallyan elevated temperature of about 100-150° C., or in a microwave.

In other embodiments, the core may be synthesized and cyclized before orafter addition of the R² subsitutent (Scheme 3). For example, such analternative route for the synthesis of benzo[d][1,2,3]triazin-4(3H)-onecompounds of Formula 2-8 (i.e., Formula II, IIA, VA, and VIIA) are shownin Scheme 3, below.

In Scheme 3, amides of Formula 3-1 can be prepared from thecorresponding acid of Formula 2-6 using an appropriately substitutedprimary amine of formula H₂N—R² under standard reaction conditions,including, but not limited to, the use of a suitable base, such asdiisopropylethylamine. In addition, the acid of Formula 2-6 can first beconverted to the corresponding acid halide using, for example,thionylchloride, prior to reaction with the amine of formula H₂N—R².Compounds of Formula 3-1 are then cyclized to afford compounds ofFormula 3-2 using sodium nitrite in the presence of an acid, such ashydrochloric acid, in a suitable solvent system, such as aqueousdioxane. Compounds of Formula 3-2 are then coupled with an appropriatelysubstituted boronic acid derivative of formula R¹Q-B(OH)₂, or a boronicester thereof, under typical coupling reaction conditions as describedhereinabove, to afford compounds of Formula 2-8.

In certain embodiments, the core may be synthesized and cyclized beforeor after addition of the R² subsitutent (Schemes 4 and 5). For example,the synthesis of 2H-benzo[e][1,3]oxazin-4(3H)-one compounds of Formula4-4 (e.g., Formula V and VIIIA) are shown in Scheme 4, below.

In Scheme 4, compounds of Formula 4-2 can be prepared from thecorresponding amide of Formula 4-1 via cyclization using a reagent ofFormula 4-5, or a protected version thereof, in the presence of an acid,such as para-toluenesulfonic acid or hydrochloric acid, in a suitablesolvent system, such as toluene, to afford compounds of Formula 4-2.Compounds of Formula 4-2 can then be coupled with an appropriatelysubstituted boronic acid derivative of formula R¹Q-B(OH)₂, or a boronicester thereof, under typical coupling reaction conditions as describedhereinabove, to afford compounds of Formula 4-3. The R² moiety may becoupled to compounds of Formula 4-3 under substitution reactionconditions with an appropriate reagent of formula LG-R² (where LG is aleaving group such as a halo, hydroxyl, alkoxy, or the like) as shown inScheme 1 to afford compounds of Formula 4-4. Typical substitutionreaction conditions include the presence of a base, such as potassiumcarbonate, sodium bicarbonate, triethylamine, and the like, in a polaraprotic solvent, such as N,N-dimethylformamide, and optionally anelevated temperature of about 100-150° C., or in a microwave.

In other embodiments, an alternative synthesis of2H-benzo[e][1,3]oxazin-4(3H)-one compounds of Formula 4-4 (e.g., FormulaV and VIIIA) is shown in Scheme 5, below.

In Scheme 5, amides of Formula 5-2 can be prepared from thecorresponding ester of Formula 5-1 using an appropriately substitutedprimary amine of formula H₂N—R² under standard reaction conditions,including, but not limited to, the use of a suitable base, such asdiisopropylethylamine. Compounds of Formula 5-2 are then cyclized toafford compounds of Formula 5-3 using a reagent of Formula 4-5, or aprotected version thereof, in the presence of an acid, such aspara-toluenesulfonic acid or hydrochloric acid, in a suitable solventsystem, such as toluene. Compounds of Formula 5-3 are then coupled withan appropriately substituted boronic acid derivative of formulaR¹Q-B(OH)₂, or a boronic ester thereof, under typical coupling reactionconditions as described hereinabove, to afford compounds of Formula 4-4.

In another embodiment, compounds of Formula 6-4 (e.g., Formula VI andIXA) can be synthesized as shown in Scheme 6, below.

In Scheme 6, compounds of Formula 6-2 can be prepared from thecorresponding 2,3-dihydro-1H-inden-1-one of Formula 6-1 using about a1.5 molar excess of sodium azide in the presence of an acid, such asmethanesulfonic acid, in an ice bath. Compounds of Formula 6-2 are thencoupled with an appropriately substituted boronic acid derivative offormula R¹Q-B(OH)₂, or a boronic ester thereof, under typical couplingreaction conditions as described hereinabove, to afford compounds ofFormula 6-3. The R² moiety may be coupled to compounds of Formula 6-3under substitution reaction conditions with an appropriate reagent offormula LG-R² (where LG is a leaving group such as a halo, hydroxyl,alkoxy, or the like) to afford compounds of Formula 6-4. Typicalsubstitution reaction conditions include the presence of a base, such aspotassium carbonate, sodium bicarbonate, triethylamine, and the like, ina polar aprotic solvent, such as N,N-dimethylformamide, and optionallyan elevated temperature of about 100-150° C., or in a microwave.

In certain embodiments, the core may be synthesized and cyclized beforeor after addition of the Q-R¹ subsitutent (Scheme 7). For example, suchroutes for the synthesis of quinazolin-4(3H)-one compounds of Formula7-5 (i.e., Formula IV, IVA and IVB) are shown in Scheme 7, below.

In one embodiment, compounds of Formula 7-2 can be provided fromcompounds of Formula 7-1. For example, compounds of Formula 7-2 arecoupled with an appropriately substituted boronic acid derivative offormula R¹Q-B(OH)₂, or a boronic ester thereof, under typical couplingreaction conditions as described hereinabove, to afford compounds ofFormula 7-2. Compounds of Formula 7-2 are then cyclized using an excessof the appropriate amide to afford compounds of Formula 7-3.

In another embodiment, compounds of Formula 7-3 are prepared fromcompounds of Formula 7-1 by way of compounds of Formula 7-4. Reaction ofcompounds of Formula 7-1 with an excess of the appropriate amide affordscompounds of Formula 7-4, which are then converted to compounds ofFormula 7-3 via reaction with an appropriately substituted boronic acidderivative of formula R¹Q-B(OH)₂, or a boronic ester thereof, undertypical coupling reaction conditions. Typical coupling reactionconditions an inert solvent, for example aqueous N,N-dimethylformamide,in the presence of a mild base, for example potassium carbonate orsodium bicarbonate. The reaction is typically conducted in the presenceof a metal catalyst with an appropriate ligand, for exampledichlorobis(triphenylphosphine) palladium(II), at a temperature of about120-170° C., for about 10 minutes to about 1 hour or at a lowertemperature, i.e., 90-110° C. for 2 to 5 days. When the reaction issubstantially complete, the compounds of Formula 7-3 can be isolated byconventional means.

The R² moiety may be coupled to compounds of Formula 7-3 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy, orthe like) as shown in Scheme 1 to afford quinazolin-4(3H)-one compoundsof Formula 7-5. Typical substitution reaction conditions include thepresence of a base, such as potassium carbonate, sodium bicarbonate,triethylamine, and the like, in a polar aprotic solvent, such asN,N-dimethylformamide, and optionally an elevated temperature of about100-150° C., or in a microwave.

In other embodiments, the core may be synthesized and cyclized before orafter addition of the R² subsitutent (Scheme 8). For example, such analternative route for the synthesis of quinazolin-4(3H)-one compounds ofFormula 7-5 (i.e., Formula IV and IVA) are shown in Scheme 8, below.

In Scheme 8, amides of Formula 3-1 can be prepared from thecorresponding acid of Formula 2-6 using an appropriately substitutedprimary amine of formula H₂N—R² according to Scheme 3, hereinabove.Compounds of Formula 3-1 are then cyclized using triethyl orthoformate(i.e., (EtO)₃CR³), or an appropriately substituted derivative thereof,to afford compounds of Formula 8-1. Compounds of Formula 8-1 are thencoupled with an appropriately substituted boronic acid derivative offormula R¹Q-B(OH)₂, or a boronic ester thereof, under typical couplingreaction conditions as described hereinabove, to affordquinazolin-4(3H)-one compounds of Formula 7-5.

Alternatively, compounds of Formula 7-4 are coupled with anappropriately substituted boronic acid derivative of formula R¹Q-B(OH)₂,or a boronic ester thereof, under typical coupling reaction conditionsas described hereinabove, to afford compounds of Formula 8-2, which canthen be further substituted with R² using an appropriate reagent offormula LG-R² (where LG is a leaving group such as a halo, hydroxyl,alkoxy, or the like) as shown in Scheme 1 to afford quinazolin-4(3H)-onecompounds of Formula 7-5.

In another embodiment, compounds of Formula 9-3 (e.g., Formula VI andIXA) can be synthesized as shown in Scheme 9, below.

Compounds of Formula 9-1 may be coupled to the —C(O)—R² moiety undertypical peptide coupling reaction conditions with an appropriate reagentof formula LG-C(O)—R² (where LG is a leaving group such as a halo,hydroxyl, alkoxy, or the like) to afford compounds of Formula 9-2.Typical coupling reaction conditions include the presence of anactivating agent, such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) with N-methylmorpholine (NMM),and the like, in a polar aprotic solvent, such as N,N-dimethylformamide,and optionally an elevated temperature of about 100-150° C., or in amicrowave. Compounds of Formula 9-1 can be purchased or synthesizedaccording to known procedures. Compounds of Formula 9-2 are then coupledwith an appropriately substituted boronic acid derivative of formulaR¹Q-B(OH)₂, or a boronic ester thereof, under typical coupling reactionconditions as described hereinabove, to afford compounds of Formula 9-3.

In another embodiment, the synthesis of2H-benzo[e][1,3]thiazin-4(3H)-one compounds of Formula 10-4 (e.g.,Formula V) are shown in Scheme 10, below.

In Scheme 4, compounds of Formula 10-2 can be prepared from thecorresponding amide of Formula 10-1 via cyclization using a reagent ofFormula 4-5, or a protected version thereof, in the presence of ammoniumacetate, in a suitable solvent system, such as toluene, to affordcompounds of Formula 10-2. Compounds of Formula 10-2 can then be coupledwith an appropriately substituted boronic acid derivative of formulaR¹Q-B(OH)₂, or a boronic ester thereof, under typical coupling reactionconditions as described hereinabove, to afford compounds of Formula10-3. The R² moiety may be coupled to compounds of Formula 10-3 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy, orthe like) to afford compounds of Formula 10-4. Typical substitutionreaction conditions include the presence of a base, such as sodiumhydride, potassium carbonate, sodium bicarbonate, triethylamine, and thelike, in a polar aprotic solvent, such as N,N-dimethylformamide, at roomtemperature, or optionally an elevated temperature of about 100-150° C.,or in a microwave.

In certain embodiments, the core may be commercially available or besynthesized or cyclized before the addition of the -Q-R¹ and/or R²subsitutent. For example, the synthesis of bromophthalazinone compoundsof Formula 11-3 (e.g., Formula III, IIIA and VIA) are shown in Scheme11, below.

In Scheme 11, compounds of Formula 11-1 can then be coupled with anappropriately substituted boronic acid derivative of formula R¹Q-B(OH)₂,or a boronic ester thereof, under typical coupling reaction conditionsas described hereinabove, to afford compounds of Formula 11-2. The R²moiety may be coupled to compounds of Formula 11-2 under substitutionreaction conditions with an appropriate reagent of formula LG-R² (whereLG is a leaving group such as a halo, hydroxyl, alkoxy, or the like) asshown in Scheme 1 to afford compounds of Formula 11-3. Typicalsubstitution reaction conditions include the presence of a base, such aspotassium carbonate, sodium bicarbonate, triethylamine, and the like, ina polar aprotic solvent, such as N,N-dimethylformamide, and optionallyan elevated temperature of about 100-150° C., or in a microwave.

It will also be appreciated that the addition of any substituent mayresult in the production of a number of isomeric products any or all ofwhich may be isolated and purified using conventional techniques. Thefollowing examples are included to demonstrate preferred embodiments ofthe invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius anal Analytical ATPAdenosine-5′-triphosphate ATX II Anemonia sulcata toxin ACN AcetonitrileBOC tert-Butoxycarbonyl CDI 1,1′-Carbonyldiimidazole CHO Chinese hamsterovary Cy Cyclohexane d Doublet dd Doublet of doublets DABAL-Me₃Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct DEAD Diethylazodicarboxylate DIEA N,N-Diisopropylethylamine DMF DimethylformamideDMSO Dimethylsulfoxide dppf 1,1′-Bis(diphenylphosphino)ferrocene dtDoublet of triplets ECF Extracellular fluid EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTAEthylenediaminetetraacetic acid EGTA Ethylene glycol tetraacetic acidequiv/eq Equivalents EtOAc Ethyl acetate EtOH Ethanol g Grams G418Geneticin GTP Guanosine-5′-triphosphate HEPES(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid) hERG humanEther-à-go-go Related Gene HPLC High-performance liquid chromatographyhrs/h Hours Hz Hertz IC₅₀ The half maximal inhibitory concentrationIMR-32 Human neuroblastoma cell line IRES Internal ribosome entry siteIU International unit J Coupling constant Kg Kilogram kHz Kilohertz LLiter LCMS/LC-MS Liquid chromatography-mass spectrometry M Molar m Meterm/z mass-to-charge ratio M+ Mass peak M + H Mass peak plus hydrogen M +Na Mass peak plus sodium Me Methyl mg Milligram MHz Megahertz min Minuteml/mL Milliliter mM Millimolar mm Millimeter mmol Millimole mOsmolMilliosmole MRM Magnetic Resonance Microscopy MS Metabolic Stability MSMass spectroscopy ms Millisecond mV Millivolt MW/mw Microwave N Normalnmol Nanomole NMR Nuclear magnetic resonance pA Picoamps Ph Phenyl prepPreparative q.s. Quantity sufficient to achieve a stated function RfRetention factor RT/rt/R.T Room temperature s Second s Singlet SEMStandard error of the mean t Triplet TB Tonic Block TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layerchromatography TTX Tetrodotoxin UDB Use Dependent Block WT Wild type δChemical shift μg Microgram μL/μl Microliter μM Micromolar μm Micrometerμmol Micromole

EXAMPLES Example 16-(4-(Trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one (CompoundII-1)

To a mixture of commercially available Compound 1-A (9.250 g, 43.03mmol) and sodium nitrite (8.909 g, 129.11 mmol) in 1,4-dioxane (40 mL)was added dropwise 2N aqueous HCl (80 mL, 160.00 mmol) with vigorousstir over a period of 30 min, during which H₂O was added twice (40 mLeach at 10th and 20th min). After completion of addition, the reactionmixture was stirred overnight, then diluted with H₂O (200 mL),sonicated, filtered, washed with H₂O (500 mL), dried to afford thedesired product as 1-B. LCMS m/z 226.0 (M+H), 228.0 (M+H+2), analHPLC>98%. ¹H NMR (400 MHz; DMSO-d₆) δ 8.30 (d, J=2.3 Hz, 1H); 8.22 (dd,J=8.6, 2.0 Hz, 1H); 8.10 (d, J=9.0 Hz, 1H).

To a solution of 1-B (1.130 g, 5.0 mmol) and4-trifluoromethylphenylboronic acid (1.544 g, 7.5 mmol) in DMF (30 mL)was added K₂CO₃ (2.073 g, 15.0 mmol) and H₂O (3 mL). The reactionmixture was stirred for 5 min under an atmosphere of dry N₂. PdCl₂(dppf)(146 mg, 0.20 mmol) was added, and the resulting mixture was heated at98° C. until 1-B disappeared (LCMS). The reaction mixture was cooled,diluted with EtOAc (70 mL), filtered through a layer of celite, washedwith 20% DMF in EtOAc (100 mL), transferred to a separation funnel,organic phase was washed with 0.5M K₂CO₃ (50 mL, 25.0 mmol), 30% aqueousNH₄Cl (100 mL) and brine (100 mL), dried and concentrated. To the crudeproduct was added 10% EtOAc in n-hexane (10 mL), sonicated, filtered,washed with 10% EtOAc in n-hexane (20 mL) to afford the desired productas Compound 1, MS m/z 308.0 (M+H), HPLC purity>97%. ¹H NMR matched thedesired product. The combined filtrate was concentrated, subjected toGilson's reverse-phase preparative HPLC with a gradient 0.1% TFAcontaining ACN/H₂O (10% to 90%) to afford additional desired product asCompound II-1. LCMS m/z 308.0 (M+H), anal HPLC>99%. The overall combinedyield is 71%. ¹H NMR (400 MHz; DMSO-d₆) δ 8.42 (m, 1H); 8.39 (d, J=2.3Hz, 1H); 8.26 (d, J=8.2 Hz, 1H); 8.00 (m, 2H); 7.52 (d, J=8.2 Hz, 2H).¹⁹F NMR (400 MHz; DMSO-d₆) δ-57.2 (s, 3F).

Example 26-(6-(2,2,2-trifluoroethoxyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-1)

Compound V-1 was prepared using a similar procedure as that describedfor Compound II-1 with the appropriate starting materials.

Example 3 6-(2-methoxypyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-4)

Compound V-4 was prepared using a similar procedure as that describedfor Compound II-1 with the appropriate starting materials.

Example 46-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-7)

Compound V-7 was prepared using a similar procedure as that describedfor Compound II-1 with the appropriate starting materials.

Example 56-(2-(dimethylamino)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-9)

Compound V-9 was prepared using a similar procedure as that describedfor Compound II-1 with the appropriate starting materials.

Example 6 6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-20)

Compound II-20 was prepared using a similar procedure as that describedfor Compound II-1 with the appropriate starting materials.

Example 73-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-14)

To a solution of Compound 1 (2.446 g, 7.96 mmol),3-(chloromethyl)-5-cyclopropyl-1,2,4-oxadiazole (1.660 g, 10.47 mmol) inDMF (15 mL) in a Biotage microwave tube (20 mL capacity) was addedpotassium carbonate (1.881 g, 13.61 mmol) and triethyl amine (2 mL) withstir. The reaction mixture was stirred at room temperature for 5 min,and then subjected to microwave heating at 120° C. until Compound 1disappeared in LCMS. The mixture was cooled, diluted with 20% DMF inEtOAc (50 mL), filtered, washed with 20% DMF in EtOAc (100 mL). Thecombined filtrate was concentrated in vacuo, dissolved mostly indichloromethane (20 mL), filtered, and the filtrated was subjected toYamazen chromatography over Universal column, eluted with a gradientEtOAc in n-hexane to afford, after drying, Compound 14, anal HPLC 97%.Compound II-14 was recrystallized from EtOAc/n-hexane and dried to giveCompound II-14: MS m/z 430.1 (M+H), 452.1 (M+Na), Analytical HPLC purity>99%.

¹H NMR (400 MHz; DMSO-d₆) δ 8.46 (m, 2H); 8.35 (d, J=9.0 Hz, 1H); 8.20(d, J=7.6 Hz, 2H); 7.53 (d, J=7.8 Hz, 2H); 5.71 (s, 2H); 2.31 (m, 1H);1.21 (m, 2H); 1.06 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d₆) δ-57.2 (s, 3F).

Example 83-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(6-(2,2,2-trifluoroethoxyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-2)

Compound V-2 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 93-((3-tert-butyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-2)

Compound II-2 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 103-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-3)

Compound II-3 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 113-((5-chloropyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-4)

Compound II-4 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 123-(1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-5)

Compound II-5 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 133-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-6)

Compound II-6 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 143-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-phenoxyphenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-7)

Compound II-7 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 153-((3-((pyridin-2-ylsulfonyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-8)

Compound II-8 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 163-((3-phenylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-10)

Compound II-10 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 17N-(2,6-dimethylphenyl)-2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetamide(Compound II-11)

Compound II-11 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 183-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-12)

Compound II-12 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 193-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-13)

Compound II-13 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 206-(4-(4-chlorophenoxyl)phenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-16)

Compound II-16 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 213-((4,5-dimethyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-23)

Compound II-23 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 223-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-24)

Compound II-24 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 233-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-25)

Compound II-25 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 243-((5-methylisoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-26)

Compound II-26 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 254-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)benzonitrile(Compound II-27)

Compound II-27 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 263-(2-(1H-pyrazol-1-yl)ethyl)-6-(4-(4-chlorophenoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-29)

Compound II-29 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 272-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetonitrile(Compound II-30)

Compound II-30 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 283-((1H-imidazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-35)

Compound II-35 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 293-benzyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-42)

Compound II-42 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 303-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-8)

Compound V-8 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 313-(but-3-ynyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-45)

Compound II-45 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 323-(1-(3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-53)

Compound II-53 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 333-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-66)

Compound II-66 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 343-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-67)

Compound II-67 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 353-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-78)

Compound II-78 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 363-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-79)

Compound II-79 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 373-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-91)

Compound II-91 was prepared using a similar procedure as that describedfor Compound II-14 with the appropriate starting materials.

Example 383-(pyrimidin-2-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-56)

2-Amino-5-bromobenzoic acid 38-A (1.4 g, 6.48 mmol) in thionyl chloride(8 mL) was stirred at 70° C. for 2 hrs. After removing the extra solventthe residue was suspended in toluene. O-(trimethylsilyl)hydroxylamine(1.98 mL, 16.2 mmol) was then added, and the mixture was stirred at roomtemperature overnight. The solvent was evaporated and the residue wassuspended in concentrated HCl (2 mL) and H₂O (15 mL). A solution ofNaNO₂ (0.89 g, 12.96 mmol) in H₂O (5 mL) was then added slowly in anice-bath. The resulting mixture was stirred at 0° C. for 1 h. Theprecipitate was collected by filtration and washed with H₂O to afford38-C.

To a stirred suspension of 38-C (145 mg, 0.6 mmol) and4-(trifluoromethoxy)phenylboronic acid (247 mg, 1.2 mmol) in DMF (3.5mL) was added NaHCO₃ (302 mg, 3.6 mmol) and H₂O (0.4 mL). Under N₂atmosphere tetrakis(triphenylphosphine)palladium (35 mg, 5%) was added.The resulting mixture was put onto microwave at 140° C. for 20 min. Themixture was diluted with EtOAc, filtered through celite and furtherwashed with EtOAc. The filtrate was concentrated and followed bypurification with HPLC to afford 38-D.

To a stirred solution of 38-D (75 mg, 0.232 mmol) in DMF (6 mL) wasadded K₂CO₃ (128 mg, 0.928 mmol), followed by 38-E (57 mg, 0.348 mmol).The resulting mixture was stirred at 70° C. overnight. Diluted thereaction mixture with EtOAc and washed with H₂O. The organic layer wasdried over Na₂SO₄ and evaporated in vacuo. The residue was then purifiedby column chromatography (EtOAc: hexanes=2:3) to afford Compound II-56.

Example 393-(pyridin-3-ylmethoxy)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-59)

Compound II-59 was prepared using a similar procedure as that describedfor Compound II-56 with the appropriate starting materials.

Example 403-(2-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-60)

Procedure to 40-B is as described in the last step for Compound II-56

To a stirred solution of 40-B (155 mg, 0.44 mmol) in THF (10 mL) wasadded 60% NaH in mineral oil (26 mg, 0.66 mmol) followed by2-chloropyrimidine-4-carbonitrile (74 mg, 0.53 mmol). The resultingmixture was stirred at 60° C. over weekend. The reaction mixture wasquenched with H₂O and extracted with EtOAc. The organic layer was driedover Na₂SO₄ and evaporated in vacuo. The residue was then purified byHPLC to afford 40-C.

Hydroxylamine hydrochloride (147 mg, 2.11 mmol) and K₂CO₃ (292 mg, 2.11mmol) were stirred in EtOH (6 mL) at room temperature for half an hour.To this mixture was added 40-C (160 mg, 0.352 mmol) in EtOH (4 mL) andthe resulting mixture was stirred at 70° C. overnight. After filtrationof inorganic salts the filtrate was concentrated in vacuo and useddirectly for next step.

A solution of cyclopropanecarbonyl chloride (55 mg, 0.528 mmol) intoluene (3 mL) was added dropwise to a solution of 40-D (0.352 mmol) inpyridine (1 mL) and toluene (2 mL). The mixture was stirred at 100° C.for two days and concentrated. The residue was purified by HPLC toafford Compound II-60.

Example 41 (R)-tert-butyl3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)pyrrolidine-1-carboxylate(Compound II-68)

To a stirred mixture of Compound II-1 (100 mg, 0.325 mmol) and 41-A (91mg, 0.488 mmol) in THF (8 mL) was added PPh₃ (170 mg, 0.65 mmol). DEAD(113 mg, 0.65 mmol) in THF (2 mL) was then added dropwise. The resultingmixture was stirred at room temperature overnight and diluted with EtOAcand washed with H₂O. The organic layer was dried over Na₂SO₄ andevaporated in vacuo. The residue was then purified by HPLC to affordCompound II-68.

Example 421-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)cyclopropanecarbonitrile(Compound II-33)

To a round bottom flask was added 2-amino-5-bromobenzoic acid (2.31mmol), and thionyl chloride (2 mL). The mixture was heated at 70° C. for2 hrs. The mixture was concentrated down under reduced pressure and theresidue was dissolved in 15 mL of CH₂Cl₂. To this solution was addeddropwise 1-aminocyclopropane carbonitrile hydrochloride salt (2.78 mmol)in CH₂Cl₂ and 2 mL of DIEA. The mixture was stirred at RT for 18 hrs andwas concentrated down before purification by preparative TLC elutingwith 5% methanol methylene chloride mixture to afford 42-A.

42-A was dissolved in 2 mL DMF followed by dropwise addition of NaNO₂(0.714 mmol) in 0.5 M HCl (4 mL). After 2 hours the reaction mixture wasconcentrated down and purified by prep TLC with 5% methanol andmethylene chloride mixture to give 42-B.

42-B was coupled with 4-trifluoromethoxyphenylboronic acid underpreviously described Suzuki conditions to give Compound II-33.

Example 433-((1-(morpholinomethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-40)

To a round bottom flask was added 2-amino-5-bromobenzoic acid (1.39mmol), and CDI or EDCI—HCl (1.5 equiv) in CH₂Cl₂ (20 mL) and the mixturewas stirred at RT for 15 min before addition of amine (1.3 equiv). Theresulting reaction mixture was stirred at RT overnight. The mixture waswashed with H₂O and the organic extract was dried over Na₂SO₄ and thenconcentrated down under reduced pressure before purification bypreparative TLC eluting with 5% methanol methylene chloride mixture toafford 43-A.

43-A was dissolved in 2 mL DMF followed by dropwise addition of NaNO₂(0.679 mmol) in 0.5 M HCl (4 mL). After 2 hours the reaction mixture wasconcentrated down and purified by prep TLC with 5% methanol andmethylene chloride mixture to give 43-B.

43-B was coupled with 4-trifluoromethoxyphenylboronic acid underpreviously described Suzuki conditions to give Compound II-40.

Example 443-((1-((2-methyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-34)

Compound II-34 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 45 methyl1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropanecarboxylate(Compound II-55)

Compound II-55 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 463-((1-((1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-58)

Compound II-58 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 473-((1-((2-ethyl-1H-imidazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-57)

Compound II-57 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 483-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-63)

Compound II-63 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 493-((1-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-64)

Compound II-64 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 503-(3-methoxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-70)

Compound II-70 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 513-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-75)

Compound II-75 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 523-(3-hydroxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-83)

Compound II-83 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 533-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-17)

Compound V-17 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 543-(3-hydroxy-2,2-dimethylpropyl)-6-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-18)

Compound V-18 was prepared using a similar procedure as that describedfor Compound II-40 with the appropriate starting materials.

Example 553-((1-((pyrimidin-2-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-80)

Compound II-75 (0.367 mmol) was dissolved in anhydrous THF undernitrogen followed by addition of NaH (0.551 mmol). The reaction mixturewas stirred at RT for 10 min after which 2-chloropyrimidine (0.735 mmol)was added. The resulting mixture was refluxed for 18 hours. The reactionwas quenched with water. Extracted with dichoromethane, dried overNa₂SO₄, and purified by prep TLC to afford Compound II-80.

Example 563-(2,2-dimethyl-3-(pyrimidin-2-yloxy)propyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-84)

Compound II-84 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 572-((1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropyl)methoxy)pyrimidine-4-carbonitrile(Compound II-88)

Compound II-88 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 583-((1-((6-chloropyridazin-3-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-89)

Compound II-89 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 593-((1-((6-(2,2,2-trifluoroethoxyl)pyridazin-3-yloxy)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-90)

Compound II-90 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 602-(2,2-dimethyl-3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)propoxy)pyrimidine-4-carbonitrile(Compound II-92)

Compound II-92 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 613-(3-(2-chloropyrimidin-4-yloxy)-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-93)

Compound II-93 was prepared using a similar procedure as that describedfor Compound II-80 with the appropriate starting materials.

Example 621-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropanecarboxylicacid (Compound II-62)

Compound II-55 (0.09 mmol) was refluxed in 1 M HCl (4 mL) and EtOH (4mL) for 72 hours. Reaction mixture was concentrated down and purified byprep TLC to afford Compound II-62.

Example 633-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-41)

2-(Piperazin-1-yl)pyrimidine (3.96 mmol) and 2-chloroacetic anhydride(4.36 mmol) were combined and refluxed in EtOH (30 mL) for 18 hours. Thereaction mixture was concentrated. The residue was dissolved indichloromethane and washed with water. The organic extract was driedover Na₂SO₄, evaporated to afford 63-A which was used in the next stepwithout further purifications.

Previously prepared6-(4-trifluoromethoxyl)phenyl)benzo[d][1,2,3]triazin-4(3H)-one (0.326mmol) was dissolved in THF under nitrogen. To this was added NaH (0.977mmol). The mixture was stirred for 10 min at RT followed by addition of63-A (0.489 mmol). After 18 hours the reaction mixture was quenched withwater and extracted with dichloromethane and purified by preparativeHPLC to give Compound II-41.

Example 643-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-10)

Compound V-10 was prepared using a similar procedure as that describedfor Compound II-41 with the appropriate starting materials.

Example 652-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide(Compound II-48)

Compound II-48 was prepared using a similar procedure as that describedfor Compound II-41 with the appropriate starting materials.

Example 666-(4-(4-chlorophenoxyl)phenyl)-3-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-65)

Compound II-65 was prepared using a similar procedure as that describedfor Compound II-41 with the appropriate starting materials.

Example 673-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-31)

To a round bottom flask was added 2-amino-5-bromobenzoic acid (1.39mmol), and CDI or EDCI—HCl (1.5 equiv) in CH₂Cl₂ (20 mL) and the mixturewas stirred at RT for 15 min before addition of amine (1.3 equiv). Theresulting reaction mixture was stirred at RT overnight. The mixture waswashed with H₂O and the organic extract was dried over Na₂SO₄ and thenconcentrated down under reduced pressure before purification bypreparative TLC eluting with 5% methanol methylene chloride mixture toafford 67-B.

To a cooled 0.5M HCl (10 mL), sodium nitrite (320 mg, 4.62 mmol) in 5 mLof water was added slowly at 0° C. and stirred at that temperature for15 min. To this mixture the amide (880 mg, 2.3 mmol) dissolved in DMF (4mL) was added slowly and stirred at room temperature for 2 h. Filteredthe precipitate, washed with water and dried and the product obtainedwas used as such for the next step.

To the bromide 67-C (1 eq), boronic acid (1.2 eq) and tetrkistriphenylphosphine palladium (10 mol %) in a microwave vial, DMF (2.5 mL) and 2NNa₂CO₃ (0.3 ml) were added and heated at 140° C. for 12 min. Aftercooling filtered through celite, concentrated and purified by prepTLC/prep HPLC. MS m/z (M⁺)=474.2.

Example 683-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-5)

Compound V-5 was prepared using a similar procedure as that describedfor Compound II-31 with the appropriate starting materials. MS m/z(M⁺)=459.2.

Example 696-(2-(dimethylamino)pyrimidin-5-yl)-3-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-6)

Compound V-6 was prepared using a similar procedure as that describedfor Compound II-31 with the appropriate starting materials. MS m/z(M⁺)=435.1.

Example 701-(4-(4-oxo-3-(2-(pyrimidin-2-yloxy)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)phenyl)cyclopropanecarbonitrile(Compound II-50)

To a solution of triazenone 70-A (2.0 g, 10 mmol) in DMF (20 mL),potassium carbonate (4.1 g, 30 mmol) and bromoethanol (3.12 g, 25 mmol)were added and heated at 90° C. for 16 h. After cooling, potassiumcarbonate was filtered off, washed with DMF and the filtrate wasconcentrated. The residue was treated with water, filtered theprecipitate, washed with water and dried and the alkylated triazenone70-B was used as such for the next step.

To a solution of triazenone alcohol 70-B (1.5 g, 5.5 mmol) and 2-chloropyrimidne (766 mg, 6.67 mmol) in THF (20 mL), sodium hydride (60%dispersion in oil, 333 mg, 8.32 mmol) was added and stirred at roomtemperature for 10 min, followed by heating at 80° C. for 24 h. Thereaction mixture was quenched with water, extracted with ethyl acetate(100 mL). The organic layer was washed with water, brine and dried oversodium sulphate and concentrated. Purification by Flash chromatographyfurnished the product 70-C.

For the Suzuki coupling reaction the following conditions were applied:To a suspension of bromide 70-C (1 eq), boronic acid or boronate ester(1.2 eq) and base potassium carbonate (3 eq) in solvent(toluene:isopropanol:water in the ratio of 4:1:1) was added palladiumcatalyst Pd(dppf)Cl₂ (10 mol %) and heated at 80° C. for 2-4 h. Thereaction progress was followed by LC and after completion, the reactionmixture was filtered through celite, washed with ethyl acetate,concentrated the filtrate and purified by prep TLC/prep HPLC. MS m/z(M⁺)=410.8.

Example 713-(2-(pyrimidin-2-yloxy)ethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-11)

Compound V-11 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials. MS m/z(M⁺)=414.8.

Example 726-(2-(piperidin-1-yl)pyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-12)

Compound V-12 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials. MS m/z(M⁺)=431.2.

Example 733-(2-(pyrimidin-2-yloxy)ethyl)-6-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-13)

Compound V-13 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials. MS m/z(M⁺)=417.2.

Example 746-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-14)

Compound V-14 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials. MS m/z(M⁺)=446.1.

Example 753-(2-(pyrimidin-2-yloxy)ethyl)-6-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-15)

Compound V-15 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials. MS m/z(M⁺)=445.1.

Example 766-(2-morpholinopyrimidin-5-yl)-3-(2-(pyrimidin-2-yloxy)ethyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-16)

Compound V-16 was prepared using a similar procedure as that describedfor Compound II-50 with the appropriate starting materials.

Example 773-(2-(5-(1H-pyrazol-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-85)

To the bromide 77-A (1 eq), boronic acid (1.2 eq) and tetrkistriphenylphosphine palladium (10 mol %) in a microwave vial, DMF (2.5 mL) and 2NNa₂CO₃ (0.3 ml) were added and heated at 140° C. for 20 min. Aftercooling filtered through celite, concentrated and purified by columnchromatography.

To a solution of triazenone alcohol 77-B (250 mg, 0.71 mmol) and2-idodo-5-bromo pyrimidne (242 mg, 0.85 mmol) in THF (20 mL), sodiumhydride (60% dispersion in oil, 50 mg, 2.13 mmol) was added and stirredat room temperature for 10 min, followed by heating at 80° C. for 3 h.The reaction mixture was quenched with water, extracted with ethylacetate (100 mL). The organic layer was washed with water, brine anddried over sodium sulphate and concentrated. Purification by prep TLCfurnished the product 77-C.

To the bromide 77-C (1 eq), boronic acid (1.2 eq) and tetrkistriphenylphosphine palladium (10 mol %) in a microwave vial, DMF (2.5 mL) and 2NNa₂CO₃ (0.3 ml) were added and heated at 140° C. for 20 min. Aftercooling filtered through celite, concentrated and purified by columnchromatography.

Example 783-(2-(5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-86)

Compound II-86 was prepared using a similar procedure as that describedfor Compound II-85 with the appropriate starting materials.

Example 793-(2-(5-(pyridin-3-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-87)

Compound II-87 was prepared using a similar procedure as that describedfor Compound II-85 with the appropriate starting materials.

Example 80 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (CompoundIII-1)

A mixture of 7-bromophthalazinone (1.09 g, 4.84 mmol),4-trifluoromethoxyphenyl boronic acid (1.20 g, 5.81 mmol), dppf(Pd)Cl₂(177 mg, 0.242 mmol), potassium carbonate (1.34 g, 9.68 mmol) indegassed toluene (4 mL), degassed water (2 mL) and degassed isopropanol(2 mL) was heated at 90° C. for 12 hours. The layers were separated, theorganic layer was concentrated and the residue was purified bytrituration with hexanes/ethyl acetate to provide7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder.C₁₅H₉F₃N₂O₂. 307.2 (M+1).

Example 812-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-2)

To a mixture of 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (50mg, 0.163 mmol), 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (47.5 mg,0.359 mmol), and potassium carbonate (68 mg, 9.68 mmol) was added DMF (1mL) and the reaction was heated to 80° C. overnight. The reaction wasdiluted with EtOAc and water, the layers were separated, and the organiclayer was concentrated to an oil. The residue was purified by flashchromatography (R_(f)=0.32, 1:1 hexanes/ethyl acetate) to afford2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-oneas a white solid. C₁₉H₁₃F₃N₄O₃. 403.1 (M+1). ¹H NMR (DMSO) δ 8.58 (s,1H), 8.48 (d, J=2.0 Hz, 1H), 8.34 (dd, J=2.0, 8.4 Hz, 1H), 8.12 (d,J=8.4 Hz, 1H), 7.98-8.02 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 5.67 (s, 2H),2.31 (s, 1H).

Example 822-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-5)

Compound III-5 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₀H₁₃F₃N₄O₂. 399.1 (M+1). ¹H NMR (DMSO) δ 8.73 (d, J=4.8 Hz, 2H), 8.51(s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 8.09 (d,J=8.0 Hz, 1H), 7.95-7.99 (m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.40 (t, J=4.8Hz, 1H), 5.55 (s, 2H).

Example 832-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-3)

Compound III-3 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₁₉H₁₃F₃N₄O₃. 403.0 (M+1). ¹H NMR (DMSO) δ 8.53 (s, 1H), 8.48 (d, J=1.6Hz, 1H), 8.32 (dd, J=2.0, 8.4 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.97-8.02(m, 2H), 7.54 (d, J=7.6 Hz, 1H), 5.48 (s, 2H), 2.56 (s, 1H).

Example 84 2-methyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-4)

Compound III-4 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₁₆H₁₁F₃N₂O₂. 321.2 (M+1)

Example 85 2-benzyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-6)

Compound III-6 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₂H₁₅F₃N₂O₂. 397.1 (M+1).

Example 862-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)benzonitrile(Compound III-7)

Compound III-7 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₃H₁₄F₃N₃O₂. 422.1 (M+1).

Example 872-phenethyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (CompoundIII-8)

Compound III-8 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₃H₁₇F₃N₂O₂. 411.0 (M+1).

Example 882-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-9)

Compound III-9 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₀H₁₅F₃N₄O₂. 401.0 (M+1). ¹H NMR (DMSO) δ 8.43 (d, J=2.0 Hz, 1H), 8.39(s, 1H), 8.26 (dd, J=2.0, 8.4 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.94-7.97(m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.34-7.35 (m, 1H), 6.14 (t, J=1.6 Hz,1H), 4.50-4.56 (m, 4H).

Example 892-(2-(1H-pyrrol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-10)

Compound III-10 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₁H₁₆F₃N₃O₂. 400.0 (M+1). ¹H NMR (DMSO) δ 8.43-8.44 (m, 1H), 8.43 (s,1H), 8.26 (dd, J=2.0, 8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.95 (dt,J=2.0, 8.8 Hz, 2H), 7.51 (d, J=7.6 Hz, 2H), 6.63 (t, J=2.0 Hz, 2H), 5.89(t, J=2.0 Hz, 2H), 4.45 (t, J=6.8 Hz, 2H), 4.32 (t, J=6.8 Hz, 2H).

Example 902-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-11)

Compound III-11 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₁₉H₁₃F₃N₄O₃. 403.1 (M+1).

Example 916-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)picolinonitrile(Compound III-12)

Compound III-12 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₂H₁₃F₃N₄O₃. 423.1 (M+1).

Example 927-(4-(trifluoromethoxy)phenyl)-2-((5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)phthalazin-1(2H)-one(Compound III-13)

Compound III-13 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₅H₁₄F₆N₄O₃. 533.1 (M+1).

Example 932-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-14)

Compound III-14 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₁H₁₃BrF₃N₃O₃. 477.9 (M+1).

Example 942-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-15)

Compound III-15 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₁₈H₁₅F₃N₂O₃. 365.0 (M+1).

Example 952-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-17)

Compound III-17 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₁H₁₇F₃N₄O₂. 415.1 (M+1). ¹H NMR (DMSO) δ 8.40-8.44 (m, 2H), 8.26 (dd,J=2.0, 8.4 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.51(d, J=8.0 Hz, 2H), 7.46 (d, J=2.0 Hz, 1H), 5.91 (d, J=2.4 Hz, 1H), 4.48(t, J=1.6 Hz, 2H), 4.42 (t, J=1.6 Hz, 2H), 2.06 (s, 3H).

Example 967-(4-(trifluoromethoxy)phenyl)-2-((6-(trifluoromethyl)pyridin-2-yl)methyl)phthalazin-1(2H)-one(Compound III-21)

Compound III-21 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₂H₁₃F₆N₃O₂. 466.1 (M+1).

Example 972-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (Compound III-25)

Compound III-25 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₅H₁₉F₃N₄O₂. 465.1 (M+1).

Example 982-(2-(1H-1,2,4-triazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-26)

Compound III-26 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₁₉H₁₄F₃N₅O₂. 401.9 (M+1).

Example 992-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-35)

Compound III-35 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₀H₁₂ClF₃N₄O₂. 433.1 (M+1). ¹H NMR (DMSO) δ 8.87 (s, 2H), 8.52 (s, 1H),8.44 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 8.09 (d, J=8.0 Hz,1H), 7.94-7.98 (m, 2H), 7.51 (d, J=7.6 Hz, 2H), 5.56 (s, 2H).

Example 1003-(2-(pyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-15)

Compound II-15 was prepared using a similar procedure as that describedfor Compound III-2 with the appropriate starting materials.C₂₁H₁₅F₃N₄O₂. 413.0 (M+1). ¹H NMR (DMSO) δ 8.38-8.44 (m, 3H), 8.26 (d,J=8.0 Hz, 1H), 8.00 (dd, J=2.4, 6.8 Hz, 2H), 7.65-7.70 (m, 1H), 7.53 (d,J=8.8 Hz, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.19-7.23 (m, 1H), 4.76 (t, J=6.8Hz, 2H), 3.30 (m, 2H).

Example 1012-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-16)

A mixture of2-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(25 mg, 0.069 mmol), Cs₂CO₃ (67 mg, 0.21 mmol) and 2-fluoropyridine (100μL) was heated to 155° C. overnight. The reaction was concentrated andpurified by reverse phase HPLC to afford2-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-oneas a white solid. C₂₃H₁₈F₃N₃O₃. 441.9 (M+1).

Example 1022-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-28)

Compound III-28 was prepared using a similar procedure as that describedfor Compound III-16 with the appropriate starting materials.C₂₁H₁₅F₃N₄O₃. 451.1 (M+23). ¹H NMR (DMSO) δ 8.52 (d, J=5.2 Hz, 2H), 8.45(s, 2H), 8.27 (dd, J=1.6, 8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96 (d,J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.8 Hz, 1H), 4.73 (t,J=5.2 Hz, 2H), 4.56 (t, J=4.8 Hz, 2H).

Example 1032-(2-(4-cyclopropylpyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-29)

Compound III-29 was prepared using a similar procedure as that describedfor Compound III-16 with the appropriate starting materials.C₂₄H₁₉F₃N₄O₃. 468.8 (M+1).

Example 1042-(2-(5-chloropyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-37)

Compound III-37 was prepared using a similar procedure as that describedfor Compound III-16 with the appropriate starting materials.C₂₁H₁₄ClF₃N₄O₃. 463.0 (M+1). ¹H NMR (DMSO) δ 8.63 (s, 2H), 8.46 (d,J=4.0 Hz, 2H), 8.27 (dd, J=2.0, 8.4 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H),7.96 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 4.73 (t, J=4.8 Hz, 2H),4.56 (t, J=4.8 Hz, 2H).

Example 1052-(2-(pyrazin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-39)

Compound III-39 was prepared using a similar procedure as that describedfor Compound III-16 with the appropriate starting materials.C₂₁H₁₅F₃N₄O₃. 428.9 (M+1). ¹H NMR (DMSO) δ 8.44 (s, 2H), 8.26 (dd,J=1.6, 8.0 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 8.09(dd, J=1.2, 2.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H),7.51 (d, J=8.0 Hz, 2H), 4.76 (t, J=5.2 Hz, 2H), 4.56 (t, J=5.2 Hz, 2H).

Example 1062-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-40)

Compound III-40 was prepared using a similar procedure as that describedfor Compound III-16 with the appropriate starting materials.C₂₂H₁₆F₃N₃O₃. 427.9 (M+1). ¹H NMR (DMSO) δ 8.45 (d, J=3.6 Hz, 2H), 8.25(dd, J=2.0, 8.0 Hz, 1H), 8.01-8.06 (m, 2H), 7.95 (d, J=9.2 Hz, 2H),7.61-7.66 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 6.88-6.93 (m, 1H), 6.71 (d,J=8.4 Hz, 1H), 4.68 (t, J=5.6 Hz, 2H), 4.53 (t, J=5.6 Hz, 2H).

Example 1072-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-18)

To a solution of -(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (52mg, 0.17 mmol), 2-(6-methylpyridin-2-yl)ethanol (30 mg, 0.22 mmol), andtriphenylphosphine (62 mg, 0.24 mmol) in THF (1 mL) was added DEAD (37μL, 0.24 mmol) and the reaction was stirred overnight. The reaction wasconcentrated and purified by reverse phase HPLC to afford2-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one.

C₂₃H₁₈F₃N₃O₂. 426.1 (M+1). ¹H NMR (DMSO) δ 8.45 (s, 2H), 8.26 (dd,J=2.0, 8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 (t, J=1.6 Hz, 1H), 7.95(t, J=2.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.25 (dd, J=4.8, 8.8 Hz, 2H), 4.47(t, J=7.6 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.37 (s, 3H).

Example 1082-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-19)

Compound III-19 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₂H₁₇F₃N₄O₄. 459.1 (M+1). ¹H NMR (DMSO) δ 8.51 (s, 1H), 8.47 (s, 1H),8.29 (dd, J=2.0, 8.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.4 Hz,2H), 7.51 (d, J=8.0 Hz, 2H), 6.12 (s, 1H), 5.36 (s, 2H), 3.71 (s, 6H).

Example 1092-((4,6-dimethylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-22)

Compound III-22 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₂H₁₇F₃N₄O₂. 427.1 (M+1). ¹H NMR (DMSO) δ 8.49 (s, 1H), 8.46 (d, J=2.0Hz, 1H), 8.29 (dd, J=2.0, 8.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.98 (t,J=2.4 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.12 (s,1H), 5.44 (s, 2H), 2.31 (s, 6H).

Example 1102-((4-cyclopropylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-23)

Compound III-23 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₃H₁₇F₃N₄O₂. 439.1 (M+1). ¹H NMR (DMSO) δ 8.49 (s, 1H), 8.45 (t, J=2.0Hz, 1H), 8.43 (s, 1H), 8.30 (dd, J=2.0, 8.0 Hz, 1H), 8.09 (d, J=8.4 Hz,1H), 7.97 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.26 (d, J=5.2 Hz,1H), 5.43 (s, 2H), 2.00-2.05 (m, 1H), 0.94-0.98 (m, 2H), 0.79-0.83 (m,2H).

Example 1112-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-24)

Compound III-24 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₂H₁₉F₃N₄O₂. 429.1 (M+1).

Example 1122-((4-(cyclopropylmethoxy)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-27)

Compound III-27 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₄H₁₉F₃N₄O₃. 469.1 (M+1).

Example 1132-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-30)

Compound III-30 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₁H₁₅F₃N₄O₃. 429.2 (M+1).

Example 1142-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-31)

Compound III-31 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₀H₁₄BrF₃N₄O₂. 479.0 (M+1).

Example 1152-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-32)

Compound III-32 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₁H₁₇F₃N₄O₂. 415.1 (M+1).

Example 1162-(2-(pyrimidin-4-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-36)

Compound III-36 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₁H₁₅F₃N₄O₂. 413.0 (M+1). ¹H NMR (DMSO) δ 9.04 (s, 1H), 8.65 (d, J=5.2Hz, 1H), 8.43 (d, J=7.2 Hz, 2H), 8.26 (dd, J=2.0, 8.0 Hz, 1H), 8.04 (d,J=8.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.44 (d,J=5.2 Hz, 1H), 4.54 (t, J=7.6 Hz, 2H), 3.24 (t, J=7.6 Hz, 2H).

Example 1172-(2-(1H-pyrazol-1-yl)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-38)

Compound III-38 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₁H₁₇F₃N₄O₂. 415.1 (M+1). ¹H NMR (DMSO) δ 8.43 (d, J=1.6 Hz, 1H), 8.35(s, 1H), 8.25 (dd, J=2.0, 8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.95 (d,J=8.8 Hz, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.34 (d,J=1.6 Hz, 1H), 6.13 (t, J=2.0 Hz, 1H) 4.91-4.97 (m, 1H), 4.39-4.49 (m,2H), 1.50 (d, J=7.2 Hz, 3H).

Example 1182-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-41)

Compound III-41 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₄H₁₅F₃N₄O₃. 465.2 (M+1).

Example 1193-(2-(pyrimidin-4-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-17)

Compound II-17 was prepared using a similar procedure as that describedfor Compound III-18 with the appropriate starting materials.C₂₀H₁₄F₃N₅O₂. 413.9 (M+1). ¹H NMR (DMSO) δ 9.04 (s, 1H), 8.67 (d, J=4.8Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.41 (dd, J=2.4, 8.8 Hz, 1H), 8.26 (d,J=8.4 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.48-7.54 (m, 3H), 4.80 (t, J=7.6Hz, 2H), 3.33 (t, J=7.6 Hz, 2H).

Example 1203-(2-(pyrimidin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-18)

Compound II-18 was prepared using a similar procedure as that describedfor Compound II-17 with the appropriate starting materials.C₂₀H₁₄F₃N₅O₂. 413.9 (M+1). ¹H NMR (DMSO) δ 8.69 (d, J=7.2 Hz, 2H), 8.45(d, J=2.0 Hz, 1H), 8.40 (dd, J=2.0, 8.8 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H),8.01 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.35 (t, J=4.8 Hz, 1H),4.84 (t, J=6.8 Hz, 2H), 3.45 (t, J=6.8 Hz, 2H).

Example 1216-(4-(trifluoromethoxy)phenyl)-3-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-52)

Compound II-52 was prepared using a similar procedure as that describedfor Compound II-17 with the appropriate starting materials.C₂₀H₁₃F₆N₅O₂. 469.9 (M+1). ¹H NMR (DMSO) δ 8.42 (d, J=2.0 Hz, 1H), 8.39(dd, J=2.0, 8.4 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.94-8.01 (m, 3H), 7.51(d, J=8.0 Hz, 2H), 6.62 (d, J=2.0 Hz, 1H), 4.78 (t, J=6.0 Hz, 2H), 4.68(t, J=6.0 Hz, 2H).

Example 1222-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-20)

A mixture of2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(25 mg, 0.053 mmol), cyclopropyl boronic acid (14 mg, 0.16 mmol),dppf(Pd)Cl₂ (6 mg, 0.0079 mmol), potassium carbonate (29 mg, 0.021 mmol)in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The layerswere separated, the organic layer was concentrated and the residue waspurified by reverse phase HPLC to provide2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-oneas a white powder. C₂₄H₁₈F₃N₃O₂. 438.1 (M+1).

Example 1232-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-34)

A mixture of2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(35 mg, 0.073 mmol), 2-methoxypyrimidin-5-ylboronic acid (13 mg, 0.087mmol), dppf(Pd)Cl₂ (2.7 mg, 0.0037 mmol), potassium carbonate (20 mg,0.015 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) anddegassed isopropanol (0.5 mL) was heated at 85° C. for 3 hours. Thelayers were separated, the organic layer was concentrated and theresidue was purified by reverse phase HPLC to provide2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-oneas a white powder. C₂₅H₁₉F₃N₆O₃. 509.2 (M+1). ¹H NMR (DMSO) δ 8.74 (s,1H), 8.38-8.44 (m, 2H), 8.26 (dd, J=2.0, 8.0 Hz, 1H), 8.20 (s, 1H), 8.03(d, J=8.4 Hz, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.84 (s, 1H), 7.51 (d, J=8.4Hz, 2H), 4.56 (s, 4H), 3.87 (s, 3H).

Example 1242-(2-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound III-33)

Compound III-33 was prepared using a similar procedure as that describedfor Compound III-34 with the appropriate starting materials.C₂₅H₁₈F₃N₅O₂. 478.2 (M+1).

Example 1253-((4,6-dimethoxypyrimidin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-44)

To a cooled (0° C.) solution of Compound II-1 (96 mg, 0.31 mmol),2-Pyrimidinemethano1,4,6-dimethoxy (64 mg, 0.37 mmol),triphenylphosphine (262 mg, 1.00 mmol) in dry THF (3.0 mL) was addeddropwise a 40 wt % of DEAD in toluene (205 uL, 0.45 mmol) under anatmosphere of nitrogen. After completion, the reaction mixture wasstirred overnight, quenched by 30% NH₄Cl (1 mL), concentrated under areduced pressure.

The crude mixture was subjected to Gilson's reverse-phase preparativeHPLC with a gradient 0.1% TFA containing ACN/H₂O (10% to 90%) to affordadditional desired product as Compound II-44. LCMS m/z 459.88 (M+H),anal HPLC>97%. ¹H NMR (400 MHz; acetone-d₆) δ 8.53 (d, J=2.0 Hz, 1H);8.44 (dd, J=8.6 and 2.0 Hz, 1H); 8.22 (d, J=8.6 Hz, 1H); 8.04 (dd, J=6.6and 2.4 Hz, 2H); 7.54 (m, 2H); 6.00 (s, 1H); 5.69 (s, 2H); 3.76 (s, 6H).¹⁹F NMR (400 MHz; acetone-d₆) δ-59.03 (s, 3F).

Example 1263-((5-phenyl-1H-tetrazol-1-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-21)

Compound II-21 was prepared using a similar procedure as that describedfor Compound II-44 with the appropriate starting materials.

Example 1273-((2H-benzo[d][1,2,3]triazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-28)

Compound II-28 was prepared using a similar procedure as that describedfor Compound II-44 with the appropriate starting materials.

Example 1283-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-47)

Compound II-47 was prepared using a similar procedure as that describedfor Compound 44 with the appropriate starting materials.

Example 1293-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-54)

Compound II-54 was prepared using a similar procedure as that describedfor Compound II-44 with the appropriate starting materials.

Example 1303-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-9)

To a solution of Compound II-1 (75 mg, 0.244 mmol), 130-A (100 mg, 0.44mmol) in DMF (3 mL) in a Biotage microwave tube (5 mL capacity) wasadded K₂CO₃ (276 mg, 2.0 mmol). The reaction mixture was sealed andsubjected to microwave heating at 140° C. for 20 min. The mixture wascooled, diluted with 20% DMF in EtOAc (20 mL), filtered, washed with 20%DMF in EtOAc (10 mL). The combined filtrate was concentrated in vacuo,dissolved mostly in DMF (2 mL), subjected to Gilson's reverse-phasepreparative HPLC with a gradient 0.1% TFA containing ACN/H₂O (5% to 95%)to afford additional desired product as Compound II-9. LCMS m/z 496.0(M+H), anal HPLC>98%. ¹H NMR (400 MHz; DMSO-d3) δ 8.48 (s, 1H); 8.41 (m,1H); 8.28 (m, 1H); 8.02 (m, 2H); 7.72 (m, 1H); 7.53 (m, 4H); 5.99 (m,1H); 5.46 (m, 1H); 4.51 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d3) δ-57.19 (s,3F).

Example 1313-(2-hydroxy-3-(2-methylbenzo[d]thiazol-6-yloxy)propyl)-6-(6-(2,2,2-trifluoroethoxyl)pyridin-3-yl)benzo[d][1,2,3]triazin-4(3H)-one(Compound V-3)

Compound V-3 was prepared using a similar procedure as that describedfor Compound II-9 with the appropriate starting materials.

Example 1322,2-dimethyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-17)

Synthesis of Compound 132-A. To a stirred solution of5-bromo-2-hydroxybenzamide (1.0 g, 4.6 mmol) in toluene (25 mL) wasadded 2,2-dimethoxypropane (1.0 g, 9.5 mmol) and p-toluene sulfonic acid(1.7 g, 10.0 mmol). The mixture was heated at 100° C. for 16 h. Thesolvent was evaporated and the residue was purified using columnchromatography.

Compound VIII-17 was prepared from Compound 132-A and4-trifluoromethoxyboronic acid under Suzuki conditions. For the Suzukicoupling reaction the following conditions were applied: To a suspensionof Compound 132-A (1 eq), the substituted boronic acid or boronate ester(1.2 eq) and base sodium bicarbonate (3 eq) in solvent (DMF:water in theratio of 4:1) was added palladium catalyst Pd(dppf)Cl₂ (10 mol %) andheated at 80° C. for 2-4 h. The reaction progress was followed by LC andafter completion, the reaction mixture was filtered through celite,washed with ethyl acetate. The filtrate was concentrated the filtrateand purified by prep TLC/prep HPLC or column chromatography.

Example 1333-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-3)

Synthesis of 133-A. To a stirred solution of DABAL-Me₃ (1.0 g, (4 mmol)in 15 mL THF was added 2-methylaminopyridine (0.40 g, 4 mmol). Themixture was stirred at 40° C. for 1 h. To the mixture was added5-bromosalicylate and the mixture was heated at reflux for 16 h. thereaction was cooled to RT and quenched with aq. HCl dropwise thenextracted with 2×25 mL EtOAc. The organic layer was washed with 10×2 mLwater and dried over MgSO₄. The solvent was removed and the residue waspurified using column chromatography.

Synthesis of 133-B. Same as synthesis of 132-A using para formaldehydein place of dimethoxypropane.

Compound VIII-3 was prepared from 133-B and 4-trifluoromethoxyboronicacid under Suzuki conditions according to Example 132.

¹H-NMR (CDCl₃) δ 8.57 (d, 1H, J=5.6 Hz), 8.19 (d, 1H, J=2.4 Hz),7.63-7.69 (m, 2H), 7.59 (dd, 2H, J=6.4, 2.0 Hz), 7.44 (d, 1H, J=8.0 Hz),7.28 (d, 2H, J=8.4 Hz), 7.23 (t, 1H, J=4.8 Hz), 7.06 (d, 1H, J=8.0 Hz),5.40 (s, 2H), 4.89 (s, 2H). MS m/z 401.0 (M+H).

Example 1343-(pyridin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-1)

Compound VIII-1 was prepared using a similar procedure as that describedfor Compound VIII-3 with the appropriate starting materials. ¹H-NMR(CD₃OD) δ 8.51 (d, 1H, J=4.4 Hz), 8.19 (d, 1H, J=2.4 Hz), 7.80-7.88 (m,4H), 7.74 (d, 2H, J=8.8 Hz), 7.47 (d, 1H, J=3.8 Hz), 7.33 (dd, 1H,J=7.6, 5.2 Hz), 7.17 (d, 1H, J=8.8 Hz), 5.45 (s, 2H), 4.90 (s, 2H); MSm/z 385.1 (M+H).

Example 1352-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound IX-1)

Compound IX-1 was prepared using the procedures disclosed in the abovescheme using the appropriate starting materials. ¹H-NMR (DMSO-d6) δ 8.75(d, 2H, J=5.2 Hz), 8.17 (d, 1H, J=2.4 Hz), 7.78 (m, 3H) 7.35-7.45 (m,4H), 4.93 (s, 1H), 3.74-3.78 (t, 2H), 3.07-3.10 (t, 2H). MS m/z 400.1(M+H).

Example 1362-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound IX-2)

Compound IX-2 was prepared using a similar procedure as that describedfor Compound IX-1 with the appropriate starting materials. ¹H-NMR(DMSO-d6) δ 8.61 (d, 1H)), 8.12 (m, 1H), 7.82 (m, 1H) 7.78-7.80 (m, 4H),7.42-7.54 (m, 4H) 4.88 (s, 1H), 3.62-3.70 (t, 2H), 3.05-3.09 (t, 2H), MSm/z 399.1 (M+H).

Example 1373-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-2)

Compound VIII-2 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1382-phenethyl-3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-4)

Compound VIII-4 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1392-phenethyl-3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-5)

Compound VIII-5 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1402-methyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-6)

Compound VIII-6 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1412-methyl-3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-7)

Compound VIII-7 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z 416.0 (M+H).

Example 1422-methyl-3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-8)

Compound VIII-8 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1432-phenethyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-9)

Compound VIII-9 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1442,2-dimethyl-3-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-10)

Compound VIII-10 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. MS m/z 429.1 (M+H).

Example 1452,2-dimethyl-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-11)

Compound VIII-11 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1466-(4-(trifluoromethoxy)phenyl)spiro[benzo[e][1,3]oxazine-2,3′-oxetan]-4(3H)-one(Compound VIII-12)

Compound VIII-12 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1472,2-dimethyl-3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-13)

Compound VIII-13 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1482,2-dimethyl-3-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-14)

Compound VIII-14 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1493-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-2,2-dimethyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-15)

Compound VIII-15 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1502,2-dimethyl-3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-16)

Compound VIII-16 was prepared using the procedures disclosed hereinabove with the appropriate starting materials.

Example 1512-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound IX-3)

Compound IX-3 was prepared using the procedures disclosed herein abovewith the appropriate starting materials.

Example 1522-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound IX-4)

Compound IX-4 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.74 (d, 2H,J=4.8 Hz), 8.09 (d, 1H, J=1.6 Hz), 7.65-7.72 (m, 5H), 7.35-7.37 (m, 2H),5.01 (s, 2H), 3.82 (t, 2H, J=6.6 Hz), 3.16 (t, 2H, J=6.6 Hz); MS m/z408.1 (M+H).

Example 1532-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound IX-5)

Compound IX-5 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.74 (d, 2H,J=5.2 Hz), 8.06 (d, 1H, J=1.2 Hz), 7.61-7.65 (m, 3H), 7.28-7.37 (m, 4H),7.53 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.32-7.38 (m, 3H), 5.01(s, 2H), 3.82 (t, 2H, J=6.6 Hz), 3.15 (t, 2H, J=6.4 Hz); MS m/z 424.1(M+H).

Example 154pyridin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-6)

To a suspension of 7-bromo-1,2,3,4-tetrahydro-isoquinoline hydrochloride(500 mgs, 2.0 mmol), pyridine-2-carboxylic acid (322 mgs, 2.61 mmol),HATU (992 mgs, 2.61 mmol), in DMF (2.5 mL) was added NMM (0.7 mL, 6.0mmol) and the resulting solution was stirred at 23° C. for 3 h. Thereaction mixture was then diluted with water/acetonitrile (15:1) and theresulting oil was then taken into EtOAc and washed with 1N HCl, NaHCO₃,brine and dried (MgSO₄). The mixture was the filtered and concentrated)to provide(7-bromo-3,4dihydroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone.

A mixture 4-(trifluoromethyl)phenylboronic acid (90 mgs, 0.48 mmol),7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone (100mgs, 0.32 mmol), potassium carbonate (87 mgs, 0.63 mmol), PdCl₂(dppf)(23 mgs, 0.03 mmol) in toluene/ethanol/water (2 mL/1 mL/1 mL) was heatedin the microwave for 30 min at 120° C. The mixture was then concentratedand chromatographed (12 grams of SiO₂, 50% EtOAc/DCM) to provide thetitle compound.

MS found for C₂₂H₁₇F₃N₂O as (M+H)⁺383.1 ¹H NMR (400 MHz, dmso-d₆):mixture of rotomers (˜1.5:1): major rotomer: 6 8.62 (d, J=4.8 Hz, 1H),7.96-7.91 (m, 3H); 7.89-7.42 (m, 6H); 7.31 (m, 1H); 4.89 (s, 2H);3.65-3.62 (m, 2H); 2.91-2.88 (m, 2H).

Example 155pyrimidin-2-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-7)

Compound IX-7 was prepared using the procedures disclosed for CompoundIX-6 with pyrimidine-2-carboxylic acid instead of pyridine-2-carboxylicacid. MS found for C₂₁H₁₆F₃N₃O as (M+H)⁺ 384.1 ¹H NMR (400 MHz,dmso-d₆): mixture of rotomers major rotomer: δ 8.93 (m, 2H), 7.96-7.91(m, 3H); 7.91-7.55 (m, 6H); 7.32 (m, 1H); 4.90 (s, 2H); 3.44-3.41 (m,2H); 2.86-2.848 (m, 2H).

Example 156(1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone(Compound IX-8)

Compound IX-8 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS found for C₂₂H₁₈F₃N₃O 398.1(M+1).

Example 1573-((2-methyloxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-95)

Compound II-95 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 403.0 (base peak, M+H+);425.0 (M+Na+) 827.2 (2M+Na+).

Example 1583-((5-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-96)

Compound II-96 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 403.0 (base peak, M+H+);827.1 (2M+Na+). ¹H-NMR δ 8.54 (d, 1H); 8.26 (d, 1H); 8.17 (dd, 1H); 7.72(d, 2H); 7.36 (d, 2H); 6.70 (s, 1H); 5.73 (s, 2H); 2.29 (s, 3H). ¹⁹F NMRδ-58.28 (s).

Example 1593-((4-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-97)

Compound II-97 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 403.1 (base peak, M+H+);827.2 (2M+Na+).

Example 1603-((2-cyclobutyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-98)

Compound II-98 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 443.1 (base peak, M+H+);907.2 (2M+Na+).

Example 1613-((2-methyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-99)

Compound II-99 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 403.1 (base peak, M+H+);827.2 (2M+Na+). ¹H-NMR δ 8.54 (d, 1H); 8.24 (d, 1H); 8.13 (dd, 1H); 7.72(d, 2H); 7.65 (s, 1H); 7.38 (d, 2H); 5.55 (s, 2H); 2.42 (s, 3H). ¹⁹F NMRδ-58.29 (s).

Example 1623-((2-cyclopropyloxazol-4-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-100)

Compound II-100 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR δ 8.52 (d, 1H); 8.24 (d,1H); 8.12 (dd, 1H); 7.72 (d, 2H); 7.56 (s, 1H); 7.39 (d, 2H); 5.53 (s,2H); 2.05 (tt, 1H); 2.06-1.98 (m, 4H). ¹⁹F NMR δ-58.29 (s).

Example 1633-((5-tert-butyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-101)

Compound II-101 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS 445.1 (base peak, M+H+);911.3 (2M+Na+).

Example 1643-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one(Compound IV-11)

Compound IV-11 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 383.1 (base peak,M+H′); 787.2 (2M+Na⁺).

Example 1653-((5-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one(Compound IV-12)

Compound IV-12 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H NMR 8.49 (d, 1H); 8.33 (s,1H); 8.02 (dd, 1H); 7.86 (d, 1H); 7.76-7.80 (m, 4H); 6.71 (s, 1H); 5.33(s, 2H); 2.30 (s, 3H). ¹⁹F NMR-63.18 (s). MS (ESI+) 386.0 (base peak,M+H⁺); 793.2 (2M+Na⁺).

Example 1663-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-13)

Compound IV-13 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H NMR 8.70 (d, 2H); 8.52 (d,1H); 8.33 (s, 1H); 8.01 (dd, 1H); 7.92 (d, 1H); 7.69 (d, 2H); 7.35 (d,2H); 7.23 (t, 1H); 5.48 (s, 2H). ¹⁹F NMR-58.31 (s). MS (ESI+) 399.0(base peak, M+H⁺); 819.2 (2M+Na⁺).

Example 1673-((5-methyloxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-14)

Compound IV-14 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H NMR 8.52 (d, 1H); 8.22 (brs, 1H); 7.99 (dd, 1H); 7.83 (d, 1H); 7.69 (d, 2H); 7.32 (d, 2H); 6.71(s, 1H); 5.31 (s, 2H); 2.30 (s, 3H). ¹⁹F NMR-58.31 (s). MS (ESI+) 402.0(base peak, M+FI′); 825.2 (2M+Na⁺).

Example 1683-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-15)

Compound IV-15 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 391.0 (M+H⁺); 803.1(base peak, 2M+Na⁺).

Example 1693-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-16)

Compound IV-16 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H NMR 8.51 (d, 1H); 8.18 (s,1H); 7.99 (dd, 1H); 7.82 (d, 1H); 7.69 (d, 2H); 7.32 (d, 2H); 5.28 (s,2H); 2.19 (quintet, 1H); 1.22 (d, 4H). MS (ESI+) 429.0 (base peak, MAI);879.2 (2M+Na⁺).

Example 1703-((3-methylisoxazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-17)

Compound IV-17 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 402.1 (base peak,M+H⁺); 825.2 (2M+Na⁺).

Example 1713-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-18)

Compound IV-18 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 403.0 (base peak,M+H⁺); 827.1 (2M+Na⁺).

Example 1723-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-19)

Compound IV-19 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 429.1 (base peak,M+H′); 879.2 (2M+Na⁺).

Example 1733-((1-methyl-1H-pyrazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-20)

Compound IV-20 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 401.1 (base peak,M+H⁺); 823.2 (2M+Na⁺).

Example 1743-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-21)

Compound IV-21 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 403.0 (base peak,M+H⁺); 827.1 (2M+Na⁺).

Example 1753-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-22)

Compound IV-22 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 403.0 (base peak,M+H⁺); 827.1 (2M+Na⁺).

Example 1762-methyl-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-23)

Compound IV-23 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS (ESI+) 417.0 (base peak,M+H⁺); 855.1 (2M+Na⁺).

Example 1773-((4-(hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-24)

A solution of 500 mg 6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one,340 mg of methyl 2-(chloromethyl)oxazole-4-carboxylate, and 220 mgpotassium carbonate in 5 mL of DMA was heated at 80° C. for 16 h. Thereaction was diluted with water and dichloromethane, aqueous layerwashed with dichloromethane, combined organic layers dried over sodiumsulphate and concentrated. The residue was recrystallized fromacetonitrile to produce methyl2-((4-oxo-6-(4-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)methyl)oxazole-4-carboxylateCompound 177-A as a white solid (420 mg). MS m/z (ESI)=446.0 (base peak,M+H¹); 891.1 (2M+H¹); 913.1 (2M+Na⁺).

To a solution of methyl2-((4-oxo-6-(4-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)methyl)oxazole-4-carboxylateCompound 177-A (200 mg) in THF (5 mL) lithium borohydride was added (10mg) and stirred for 1 hour. Quenched with saturated ammonium chlorideand extracted with dichloromethane. Purified by gradient chromatography0 to 5% MeOH in dichloromethane and resulting3-((4-(hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-oneCompound 177-B (130 mg) submitted into next step. ¹H NMR (δ, dmso-d₆,400 MHz): 7.92 (d, 1H); 7.86 (s, 1H); 7.71 (d, 2H); 7.65 (dd, 1H); 7.38(d, 2H); 7.03 (br s, 1H); 6.85 (d, 1H); 5.14 (t, 1H); 4.74 (s, 4H); 4.32(d, 2H). ¹⁹F NMR (δ, dmso-d₆, 376 MHz): −57.29 (s). MS m/z (ESI)=420.1(base peak, M+H⁺); 861.2 (2M+Na⁺).

3-((4-(Hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-oneCompound 177-B (120 mg) was stirred in ethyl acetate (20 mL) in thepresence of palladium on carbon (10%, 120 mg) for 16 hours, thenfiltered through Celite® and purified by reverse-phase (ACN/H₂O with0.1% TFA) followed by neutralization on resin column to produce 44 mg of3-[4-(hydroxymethyl)oxazo]-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-oneCompound IV-24 as a white solid.

¹H NMR (δ, CDCl₃, 400 MHz): 8.51 (d, 1H); 8.21 (s, 1H); 8.00 (dd, 1H);7.83 (d, 1H); 7.70 (d, 2H); 7.59 (s, 1H); 7.27 (d, 2H); 5.33 (s, 2H);4.58 (s, 2H); 1.90 (br s, 1H). ¹⁹F NMR (δ, CDCl₃, 376 MHz): −58.31. MSm/z (ESI)=418.0 (base peak, M+H⁺); 857.2 (2M+Na⁺).

Example 1783-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-25)

6-Bromoquinazolin-4(3H)-one Compound 178-A (1.0 g), 2-bromoethanol (1.1g), and potassium carbonate (610 mg) were heated in DMA (10 mL) at 80°C. for 16 h. Reaction was extracted with water and dichloromethane (3times), combined organic layers washed with brine, over sodium sulphateand concentrated. Residue was triturated with acetonitrile to yield6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound 178-B (810 mg)as a white solid. MS m/z (ESI)=268.9 (base peak, ⁷⁹Br-M+H⁺); 270.9(⁸¹Br-M+H⁺); 290.9 (⁷⁹Br-M+Na⁺); 292.9 (⁸¹Br-M+Na⁺).

In an ice bath, 6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound178-B (400 mg) was dissolved in DMF (10 mL) and NaH (60% suspension inoil, 120 mg) added as one portion. After 20 min, 2-chloropyridine (250mg) was added. After 1 h, reaction was quenched by addition of water andprecipitate filtered, resulting in 450 mg of6-bromo-3-(2-(pyrimidin-2-yloxy)ethyl)quinazolin-4(3H)-one Compound178-C as off-white solid. MS m/z (ESI)=346.6 (base peak, ⁷⁹Br-M−H⁺);348.6 (⁸¹Br-M+H⁺); 368.5 (⁷⁹Br-M+Na⁺); 370.5 (⁸¹Br-M+Na⁺); 714.2(⁷⁹Br₂-2M+Na⁺); 716.2 (base peak, ⁷⁹Br⁸¹Br-2M+Na⁺); 718.3 (⁸¹Br₂-M+Na⁺).

A mixture of 60 mg6-bromo-3-(2-(pyrimidin-2-yloxy)ethyl)quinazolin-4(3H)-one Compound178-C (0.25 mmol), 53 mg 4-(trifluoromethoxy)phenyl boronic acid (0.38mmol), 18 mg potassium carbonate (0.15 mmol), and 3 mg Pd(dppf)Cl₂ in 5mL of degassed 9:1 DMF:water solution was heated at 90° C. After 1 h,the reaction mixture was filtered through celite and the filtrateconcentrated and purified by reverse-phase (ACN/H₂O with 0.1% TFA)followed by neutralization on resin column to produce 56 mg of3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-oneCompound IV-25.

¹H NMR (δ, CDCl₃, 400 MHz): 8.51 (d, 1H); 8.47 (d, 2H); 8.20 (s, 1H);7.98 (dd, 1H); 7.77 (d, 1H); 7.69 (d, 2H); 7.33 (d, 2H); 6.93 (t, 1H);4.75 (t, 2H); 4.47 (t, 2H). ¹⁹F NMR (δ, CDCl₃, 376 MHz): −58.31 (s). MSm/z (ESI)=429.1 [M+H]⁺, 879.2 [2M+Na]⁺

Example 1793-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one(Compound IV-26)

Compound IV-26 was prepared using a similar procedure as that describedfor Compound IV-25 with the appropriate starting materials. ¹H NMR (δ,CDCl₃, 400 MHz): 8.56 (d, 1H); 8.50 (d, 2H); 8.33 (s, 1H); 8.01 (dd,1H); 7.84 (d, 1H); 7.80 (d, 2H); 7.74 (d, 2H); 6.98 (t, 1H); 4.78 (t,2H); 4.50 (t, 2H). ¹⁹F NMR (δ, CDCl₃, 376 MHz): −63.03 (s). MS m/z(ESI)=413.1 [M+H]⁺, 847.2 [2M+Na]⁺

Example 1803-((1-(hydroxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-27)

To a round bottom flask was added 2-amino-5-bromobenzoic acid (6.94mmole), and CDI or EDCI—HCl (1.5 equiv) in CH₂Cl₂ (100 mL) and themixture was stirred at RT for 15 min before addition of amine (1.4equiv). The resulting reaction mixture was stirred at RT overnight. Themixture was washed with H₂O and the organic extract was dried overNa₂SO₄ and then concentrated down under reduced pressure beforepurification by biotage column chromatography eluting with 5% methanolmethylene chloride mixture to afford 1.35 grams of Compound 180-A.

Compound 180-A (0.107 mmol) was dissolved in 5 mL EtOH followed bytriethylorthoformate (0.7 mL). The reaction mixture was heated at 100 Covernight to give Compound 180-B. The mixture was then concentrated downand used in the next step without further purification.

Compound 180-B was coupled with 4-trifluoromethoxyphenylboronic acidunder previously described Suzuki conditions to give Compound IV-27.

¹H-NMR (DMSO) 0.432-0.458 (m, 2H), 0.677-0.702 (m, 2H), 3.23 (s, 2H),4.05 (s, 2H), 7.47-7.49 (d, 2H, J, =8 Hz), 7.76-7.78 (d, 1H, J, =8 Hz),7.89-7.92 (m, 2H), 8.138.16 (m, 1H), 8.37-8.37 (s, 2H), MS m/z 391.1(M⁺).

Example 1813-(3-hydroxy-2,2-dimethylpropyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-28)

To a round bottom flask was added 5-bromoisatoic anhydride (6.20 mmole)and 3-amino-2,2-dimethylpropan-1-ol (12.4 mmole) in CH₂Cl₂ (100 mL). Theresulting reaction mixture was stirred at RT overnight. The work up andpurification is similar to that described above for synthesis ofCompound IV-27.

Compound 181-A was dissolved in 5 mL EtOH followed bytriethylorthoformate. he reaction mixture was heated at 100 C overnightto give Compound 181-B as described for Compound IV-27.

Compound 181-B was coupled with 4-trifluoromethoxyphenylboronic acidunder previously described Suzuki conditions to give Compound IV-28. MSm/z 393.1 (M⁺).

Example 1823-(2,2-dimethyl-3-(pyrimidin-2-yloxy)propyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-29)

Compound IV-28 (0.367 mmole) was dissolved in THF (10 mL). To this wasadded NaH (0.551 mmole, 60% dispersion in mineral oil). To thissuspension was added 2-chloropyrimidine (0.735 mmole) and the mixturewas refluxed for 24 hours. Quenched with water and extracted withdichloromethane. Dried over Na₂SO₄ and purified by preparative TLCeluting with 2:1 Hexane:Ethyl Acetate to give Compound IV-29. MS m/z471.1 (M⁺).

Example 183(1-methyl-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-56)

Compound IX-56 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 386.1.

Example 184(1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-57)

Compound IX-57 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H NMR (400 MHz; CD₃OD) δ7.65-7.77 (m, 4H); 7.61 (s, 2H); 7.51 (m, 2H); 7.29 (m, 1H); 4.95 (m,2H); 3.96 (m, 2H); 3.02 (m, 2H). ¹⁹F NMR (400 MHz; CD₃OD) δ-64.40 (s,3F). Mass (M+H)⁺ 372.1.

Example 185(4-fluoro-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-59)

Compound IX-59 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 390.1.

Example 186(1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-80)

Compound IX-80 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 386.1. ¹H NMR (400MHz; dmso-d₆) δ 7.45-7.95 (m, 7H); 7.24 (s, 1H); 7.32 (m, 1H); 7.13 (m,1H); 5.10 (s, 1H); 4.84 (m, 1H); 3.79 (m, 3H); 2.92 (m, 4H). ¹⁹F NMR(400 MHz; DMSO-d6) δ-64.40 (s, 3F).

Example 1872-(1-methyl-1H-imidazol-4-ylsulfonyl)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(Compound IX-98)

Compound IX-98 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 422.1.

Example 188 (R)-tert-butyl2-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carboxylate(Compound IX-114)

Compound IX-114 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 475.1.

Example 189(3-amino-1H-1,2,4-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-111)

Compound IX-111 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 388.1.

Example 190(1-phenyl-1H-1,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-116)

Compound IX-116 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 449.1.

Example 191 ethyl2-(4-(7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)acetate(Compound IX-119)

Compound IX-119 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 459.1.

Example 192(1-isopropyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-27)

Compound IX-27 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 414.1.

Example 193(1,3-dimethyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-28)

Compound IX-28 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 400.1.

Example 1942-(pyridin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone(Compound IX-29)

Compound IX-29 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 397.1.

Example 1952-(pyrimidin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone(Compound IX-30)

Compound IX-30 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 398.1.

Example 196(2-isopropylpyrimidin-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-31)

Compound IX-31 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 426.1.

Example 197pyrimidin-4-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-32)

Compound IX-32 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 384.1.

Example 198pyrimidin-5-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-33)

Compound IX-33 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 384.1.

Example 199(2-amino-6-methylpyrimidin-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-34)

Compound IX-34 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 413.1.

Example 200(1H-pyrazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-36)

Compound IX-36 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 372.1.

Example 201(1-methyl-1H-imidazol-4-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-39)

Compound IX-39 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass (M+H)⁺ 386.1.

Example 202pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-11)

Similar procedure for the synthesis of Compound 1 was followed to obtainthe title compound using 4-(trifluoromethoxy)phenylboronic acid insteadof 4-(trifluoromethyl)phenylboronic acid. MS found for C₂₁H₁₆F₃N₃O₂ as(M+H)⁺ 400.1 ¹H NMR (400 MHz, dmso-d₆): mixture of rotomers (˜1.5:1):major rotomer: δ 8.93 (m, 2H), 7.80 (d, J=8.4 Hz, 2H); 7.96-7.91 (m,6H); 4.89 (s, 2H); 3.44-3.41 (m, 2H); 2.85-2.848 (m, 2H).

Example 203 Compound IX-17

7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester:To a solution of 7-bromo-1,2,3,4-tetrahydro-isoquinoline hydrochloride(1.0 g, 4.0 mmol) in DCM (18 mL) and 2M aqueous Na₂CO₃ solution (5.0 mL,10.0 mmol) was added a solution of BOC-anhydride (1.0 g, 4.6 mmol) inDCM (7 mL), The reaction mixture was stirred at RT for 3 h and thendiluted with water and DCM (1:1, 100 mL). The organic phase was thenseparated and washed with brine, dried (MgSO₄) and filtered. The solventwas evaporated and then carried to next step without purification.

tert-Butyl7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate:A mixture 4-(trifluoromethyl)phenylboronic acid (987 mgs, 5.2 mmol),7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(1.2 g, 4.0 mmol), potassium carbonate (1.1 g, 8.0 mmol), PdCl₂(dppf)(146 mgs, 0.2 mmol) in toluene/ethanol/water (3 mL/1.5 mL/1.5 mL) washeated in pressure vessel at 120° C. for 2 h. The mixture was thenconcentrated and chromatographed (40 grams of SiO₂, 30% EtOAc/hexanes)to provide the title compound (1.4 g, 92% yield over two steps).

7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride: To a solution of tert-butyl7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.4 g, 3.7 mmol) in DCM (3 mL) was added 4.0M HCl in dioxane (4.6 mL,18.56 mmol) and stirred at rt for 3 h, Diethylether (200 mL) was thenadded and the mixture was stirred at rt for 30 min and then filtered andwashed with diethylether and dried to give the title compound (1.3grams).

Pyridazin-3-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl) methanone: To a suspension of7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride (50 mgs, 0.16 mmol), pyridazine-3-carboxylic acid (30 mgs,0.24 mmol), HATU (91 mgs, 0.24 mmol), in DMF (1.0 mL) was added NMM(0.05 mL, 0.48 mmol) and the resulting solution was stirred at 23° C.for 16 h. The reaction mixture was then diluted with water/acetonitrile(10:1) and the solid formed was then washed with water, diethylether anddried to give the title compound. MS found for C₂₁H₁₆F₃N₃O as (M+H)⁺384.1 ¹H NMR (400 MHz, dmso-d₆): mixture of rotomers (˜1.5:1): majorrotomer: δ 8.93 (m, 2H), 7.96-7.91 (m, 3H); 7.91-7.55 (m, 6H); 7.32 (m,1H); 4.90 (s, 2H); 3.44-3.41 (m, 2H); 2.86-2.848 (m, 2H).

Example 204(7-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone(Compound IX-22)

Similar procedure for the synthesis of Compound II-1 was followed toobtain the title compound using2-fluoro-4-(trifluoromethyl)phenylboronic acid instead of4-(trifluoromethyl)phenylboronic acid. MS found for C₂₁H₁₅F₄N₃O 402.1(M+1).

Example 205(7-(4-chloro-2-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone(Compound IX-23)

Similar procedure for the synthesis of Compound II-1 was followed toobtain the title compound using 2-fluoro-4-Chlorophenylboronic acidinstead of 4-(trifluoromethyl)phenylboronic acid. MS found forC₂₀H₁₅FN₃O 368.1 (M+1).

Example 206(7-(4-chloro-3-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-2-yl)methanone(Compound IX-24)

Similar procedure for the synthesis of Compound II-1 was followed toobtain the title compound using 3-fluoro-4-Chlorophenylboronic acidinstead of 4-(trifluoromethyl)phenylboronic acid. MS found forC₂₀H₁₅FN₃O 368.1 (M+1).

Example 207(3-fluoropyridin-2-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-25)

Compound IX-25 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. Mass 401.1 (M+1).

Example 2083-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-1)

Compound X-1 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.52 (d, 1H,J=5.2 Hz), 8.30 (s, 1H), 7.81-7.85 (m, 1H), 7.75-7.77 (m, 3H), 7.53 (d,1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.32-7.38 (m, 3H), 4.99 (s, 2H),4.89 (s, 2H); MS m/z 417.1 (M+H).

Example 2093-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-2)

5-Bromo-2-mercaptobenzoic acid (466 mg, 2.0 mmol), paraformaldehyde (90mg, 3.0 mmol) and ammonium acetate (308 mg, 4.0 mmol) were stirred intoluene (12 mL) at 120° C. overnight. The reaction mixture wasconcentrated and purified by HPLC to afford 243-A (181 mg).

Compound X-2 was prepared using the procedures disclosed above. ¹H-NMR(CD₃OD) δ 8.76 (d, 2H, J=5.2 Hz), 8.27 (s, 1H), 7.74-7.76 (m, 3H), 7.49(d, 1H, J=8.4 Hz), 7.35-7.39 (m, 3H), 5.11 (s, 2H), 5.00 (s, 2H); MSm/z. 418.1 (M+H).

Example 2103-(pyridin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-3)

Compound X-3 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.53 (d, 1H,J=5.2 Hz), 8.36 (s, 1H), 7.75-7.87 (m, 6H), 7.52 (t, 2H, J=7.8 Hz), 7.34(t, 1H, J=6.4 Hz), 5.00 (s, 2H), 4.90 (s, 2H); MS m/z 401.0 (M+H).

Example 2113-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-4)

Compound X-4 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H,J=7.6 Hz), 8.32 (s, 1H), 7.75-7.86 (m, 5H), 7.52 (d, 1H, J=8.0 Hz),7.37-7.39 (m, 1H), 5.11 (s, 2H), 5.01 (s, 2H); MS m/z 402.1 (M+H).

Example 2123-(2-chlorobenzyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-5)

Compound X-5 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.37 (s, 1H),7.87 (d, 2H, J=8.4 Hz), 7.76-7.81 (m, 3H), 7.50-7.56 (m, 2H), 7.45 (d,1H, J=7.6 Hz), 7.30-7.40 (m, 2H), 5.00 (s, 2H), 4.85 (s, 2H); MS m/z434.0 (M+H).

Example 2133-((3-fluoropyridin-2-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-6)

Compound X-6 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.36 (d, 1H,J=4.4 Hz), 8.33 (s, 1H), 7.85 (d, 2H, J=8.0 Hz), 7.75-7.80 (m, 3H),7.58-7.63 (m, 1H), 7.50 (d, 1H, J=8.4 Hz), 7.39-7.41 (m, 1H), 5.10 (s,2H), 4.94 (s, 2H); MS m/z 419.0 (M+H).

Example 2143-((3-fluoropyridin-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one(Compound X-9)

Compound X-9 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.36 (d, 1H,J=4.4 Hz), 8.27 (s, 1H), 7.73-7.76 (m, 3H), 7.58-7.63 (m, 1H), 7.47 (d,1H, J=8.0 Hz), 7.35-7.42 (m, 3H), 5.09 (s, 2H), 4.93 (s, 2H); MS m/z435.1 (M+H).

Example 2156-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-18)

Compound VIII-18 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d,2H, J=4.8 Hz), 8.10 (s, 1H), 7.80 (d, 1H, J=8.4 Hz), 7.73 (t, 1H, J=7.6Hz), 7.55-7.61 (m, 2H), 7.37-7.39 (m, 1H), 7.21 (d, 1H, J=8.8 Hz), 5.61(s, 2H), 5.04 (s, 2H); MS m/z 404.0 (M+H).

Example 2163-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-19)

Compound VIII-19 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d,2H, J=4.4 Hz), 8.18 (d, 1H, J=2.4 Hz), 7.89 (dd, 1H, J=8.6, 2.2 Hz),7.83 (d, 2H, J=8.4 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=4.8 Hz),7.20 (d, 1H, J=8.8 Hz), 5.60 (s, 2H), 5.04 (s, 2H); MS m/z 386.0 (M+H).

Example 2173-(pyrimidin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-20)

Compound VIII-20 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d,2H, J=4.8 Hz), 8.12 (d, 1H, J=2.4 Hz), 7.83 (dd, 1H, J=8.6, 2.2 Hz),7.72 (d, 2H, J=8.4 Hz), 7.35-7.39 (m, 3H), 7.17 (d, 1H, J=8.4 Hz), 5.58(s, 2H), 5.04 (s, 2H); MS m/z 402.0 (M+H).

Example 2183-benzyl-6-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-21)

Compound VIII-21 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.23 (d,1H, J=2.4 Hz), 7.87 (dd, 1H, J=8.6, 2.2 Hz), 7.83 (d, 2H, J=8.4 Hz),7.75 (d, 2H, J=8.0 Hz), 7.29-7.39 (m, 5H), 7.15 (d, 1H, J=8.8 Hz), 5.29(s, 2H), 4.80 (s, 2H); MS m/z 384.0 (M+H).

Example 2193-benzyl-6-(2-fluoro-4-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-22)

Compound VIII-22 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.15 (s1H), 7.72-7.78 (m, 2H), 7.56-7.61 (m, 2H), 7.30-7.38 (m, 5H), 7.136 (d,1H, J=8.8 Hz), 5.30 (s, 2H), 4.80 (s, 2H); MS m/z 402.0 (M+H).

Example 2203-benzyl-6-(4-(trifluoromethoxy)phenyl)-2H-benzo[e][1,3]oxazin-4(3H)-one(Compound VIII-23)

Compound VIII-23 was prepared using the procedures disclosed hereinabove with the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.17 (d,1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.4, 2.4 Hz), 7.73 (d, 2H, J=8.4 Hz),7.30-7.38 (m, 7H), 7.13 (d, 1H, J=8.4 Hz), 5.28 (s, 2H), 4.80 (s, 2H);MS m/z 400.0 (M+H).

Example 221N-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-41)

Compound IX-41 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 411 (MH⁺).

Example 222N-phenyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-42)

Compound IX-42 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 397 (MH⁺).

Example 223N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-44)

Compound IX-44 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 361 (MH⁺).

Example 224N-(furan-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-48)

Compound IX-48 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 401 (MH⁺). ¹H NMR(DMSO-d₆): δ 7.87 (d, J=8 Hz, 2H), δ 7.80 (d, J=8.4 Hz, 2H), δ 7.57-7.51(m, 2H), δ 7.50 (s, 1H), δ 7.50 (s, 1H), δ 7.29 (d, J=7.6 Hz, 1H), δ7.09 (t, J=5.6 Hz, 1H), δ 6.36 (s, 1H), δ 6.18 (d, J=2.4 Hz, 1H), δ 4.60(s, 2H), δ 4.26 (d, J=5.6 Hz, 2H), δ 3.60 (t, J=5.8 Hz, 2H), δ 2.82 (t,J=5.8 Hz, 2H).

Example 225N-cyclopentyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-77)

Compound IX-77 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 389 (MH⁺).

Example 226N-methyl-N-phenyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-50)

Compound IX-50 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 411 (MH⁺).

Example 227morpholino(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-52)

Compound IX-52 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 391 (MH⁺).

Example 228pyrrolidin-1-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-53)

Compound IX-53 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 375 (MH⁺). ¹H NMR(DMSO-d₆): δ 7.87 (d, J=8 Hz, 2H), δ 7.80 (d, J=8.4 Hz, 2H), δ 7.56 (s,1H), δ 7.53 (d, J=7.6 Hz, 1H), δ 7.29 (d, J=7.6 Hz, 1H), δ 4.45 (s, 2H),δ 3.46 (t, J=5.6 Hz, 2H), δ 4.10-4.05 (m, 4H), δ 2.87 (t, J=5.6 Hz, 2H),δ 1.81-1.73 (m, 4H).

Example 229azetidin-1-yl(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-88)

Compound IX-88 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 361 (MH⁺).

Example 230N-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-89)

Compound IX-89 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 413 (MH⁺). ¹H NMR(DMSO-d₆): δ 8.74 (d, J=4.8 Hz, 2H), δ 7.88 (d, J=8 Hz, 2H), δ 7.80 (d,J=8.0 Hz, 2H), δ 7.55 (d, J=8.4 Hz, 1H), δ 7.52 (s, 1H), δ 7.36 (t,J=4.8 Hz, 1H), δ 7.31 (d, J=8.0 Hz, 1H), δ 7.18 (t, J=5.4 Hz, 1H), δ4.63 (s, 2H), δ 4.45 (d, J=5.6 Hz, 2H), δ 3.65 (t, J=5.8 Hz, 2H), δ 2.87(t, J=5.6 Hz, 2H).

Example 231(3-methylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-90)

Compound IX-90 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 389 (MH⁺).

Example 232(3-hydroxypyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanoneo(Compound IX-91)

Compound IX-91 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 391 (MH⁺).

Example 233(3,3-difluoroazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-92)

Compound IX-92 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 397 (MH⁺).

Example 234(3-fluoropyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-94)

Compound IX-94 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 393 (MH⁺). ¹H NMR(DMSO-d₆): δ 7.88 (d, J=8 Hz, 2H), δ 7.80 (d, J=8.0 Hz, 2H), δ 7.58 (s,1H), δ 7.54 (d, J=7.2 Hz, 1H), δ 7.29 (d, J=8.0 Hz, 1H), δ 5.31 (d,J=52.8 Hz, 1H), δ 4.48 (s, 2H), δ 3.78-3.29 (m, 6H), δ 3.00-2.90 (m,1H), δ 2.81 (dt, J=16.4 Hz, J′=5.0 Hz, 1H), δ 2.17-1.88 (m, 2H).

Example 235(3-fluoroazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-95)

Compound IX-95 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 379 (MH⁺).

Example 236(S)-(2-(hydroxymethyl)pyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-102)

Compound IX-102 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 405 (MH⁺).

Example 237(3-(methylsulfonyl)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-104)

Compound IX-104 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 439 (MH⁺).

Example 238(2R,5R)-2,5-dimethylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-105

Compound IX-105 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 403 (MH⁺). ¹H NMR(DMSO-d₆): δ 7.88 (d, J=8.4 Hz, 2H), δ 7.80 (d, J=8.0 Hz, 2H), δ 7.59(s, 1H), δ 7.54 (d, J=7.2 Hz, 1H), δ 7.29 (d, J=8.0 Hz, 1H), δ 4.50 (d,J=16.4 Hz, 1H), δ 4.43 (d, J=16.4 Hz, 1H), δ 3.99-3.90 (m, 2H), δ 3.68(dt, J=13.2 Hz, J′=4.8 Hz, 1H), δ 3.35-3.25 (m, 1H), δ 2.98-2.88 (m,1H), δ 2.77 (dt, J=16.8 Hz, J′=4.8 Hz, 1H), δ 2.14-2.03 (m, 2H), δ1.47-1.37 (m, 2H), δ 1.01 (d, J=6.0 Hz, 6H).

Example 239(2R,5S)-2,5-dimethylpyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-106

Compound IX-106 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 403 (MH⁺).

Example 240(3-methylazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-107)

Compound IX-107 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 375 (MH⁺).

Example 241(3-hydroxyazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-108)

Compound 291-A (0.050 g, 0.16 mmol), Triethylamine (0.15 mL, 1.08 mmol)were dissolved in THF (1 mL). Triphosgene (0.052 g, 0.18 mmol) in THF (1mL) was added at 0° C. with stirring in the protection of nitrogen. Theresulting mixture was stirred at room temperature for several hours.Azetidin-3-ol hydrochloride (0.021 g, 0.19 mmol) and Triethylamine (0.15mL) were added. The resulting mixture was stirred overnight,concentrated and purified by preparative HPLC to afford Compound IX-108(0.021 g, 35%).

¹H NMR (DMSO-d₆): δ 7.88 (d, J=8.4 Hz, 2H), δ 7.80 (d, J=8.4 Hz, 2H), δ7.59 (s, 1H), δ 7.54 (d, J=7.6 Hz, 1H), δ 7.29 (d, J=8.0 Hz, 1H), δ 5.58(d, J=6.4 Hz, 1H), δ 4.49 (s, 2H), δ 4.46-4.36 (m, 1H), δ 4.12 (t, J=7.8Hz, 2H), δ 3.71 (q, J=4.5 Hz, 2H), δ 3.48 (t, J=5.8 Hz, 2H), δ 2.82 (t,J=5.8 Hz, 2H). MS m/z: 377 (MH⁺).

Example 242(3-hydroxy-3-methylazetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-112)

Compound IX-112 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 391 (MH⁺).

Example 243(3-(hydroxymethyl)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-113)

Compound IX-113 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 391 (MH⁺).

Example 244pyrrolidin-1-yl(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-122)

Compound IX-122 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 391 (MH⁺). ¹H NMR(DMSO-d₆): δ 7.77 (d, J=8.8 Hz, 2H), δ 7.49 (s, 1H), δ 7.47 (d, J=7.6Hz, 1H), δ 7.43 (d, J=8.4 Hz, 2H), δ 7.24 (d, J=8.0 Hz, 1H), δ 4.43 (s,2H), δ 3.46 (t, J=5.8 Hz, 2H), δ 3.37-3.28 (m, 4H), δ 2.85 (t, J=5.6 Hz,2H), δ 1.81-1.73 (m, 4H).

Example 245N-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide(Compound IX-123)

Compound IX-123 was prepared using the procedures disclosed herein abovewith the appropriate starting materials. MS m/z: 429 (MH⁺).

The following compounds were prepared using the procedures disclosedherein above using the appropriate starting materials.

3-(2-(4-fluorophenoxyl)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-19)

3-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-22)

3-(2-(pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-32)

2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)ethoxy)pyrimidine-4-carbonitrile(Compound II-36)

tert-butyl4-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine-1-carboxylate(Compound II-37)

3-(piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-38)

3-(1-(pyrimidin-2-yl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-39)

3-(2-methoxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-43)

3-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-46)

N-cyclopropyl-2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetamide(Compound II-49)

2-(2-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)ethoxy)pyrimidine-5-carbonitrile(Compound II-51)

3-((1-(phenoxymethyl)cyclopropyl)methyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-61)

3-(2-(4-(2H-tetrazol-5-yl)pyrimidin-2-yloxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-69)

3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-71)

ethyl4-oxo-3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine-1-carboxylate(Compound II-72)

6-(4-cyclopropylphenyl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-73)

(S)-tert-butyl3-(4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)pyrrolidine-1-carboxylate(Compound II-74)

(R)-3-(pyrrolidin-3-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-76)

(S)-3-(pyrrolidin-3-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-77)

(S)-3-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-81)

(R)-3-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound II-82)

2-((1-((4-oxo-6-(4-(trifluoromethoxy)phenyl)benzo[d][1,2,3]triazin-3(4H)-yl)methyl)cyclopropyl)methoxy)pyrimidine-4-carboxamide (CompoundII-94)

6-(3-chloro-4-fluorophenyl)quinazolin-4(3H)-one (Compound IV-1)

6-(3′-chloro-4′,6-difluorobiphenyl-3-yl)quinazolin-4(3H)-one (CompoundIV-2)

3-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-3)

3-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-6-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-4)

2-methyl-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-5)

3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-6)

6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one (Compound IV-7)

3-(2-hydroxy-3-(2-methoxyphenoxyl)propyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-8)

3-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one(Compound IV-9)

6-(4-(trifluoromethoxy)phenyl)-3-((5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)quinazolin-4(3H)-one(Compound IV-10)

4-methyl-6-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (CompoundVI-1)

2-(2-(1H-pyrazol-1-yl)ethyl)-4-methyl-6-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one(Compound VI-2)

3-(2-(pyrimidin-2-yloxy)ethyl)-6-((4-(trifluoromethoxy)phenyl)ethynyl)benzo[d][1,2,3]triazin-4(3H)-one(Compound VII-1)

(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone(Compound IX-26)

(3-(pyridin-3-yloxy)azetidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-93)

(R)-(3-(hydroxymethyl)pyrrolidin-1-yl)(7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone(Compound IX-101)

Example 246

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Example 247

A tablet Formula Is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

Example 248

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Example 249

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg  Starch 45.0mg  Microcrystalline cellulose 35.0 mg  Polyvinylpyrrolidone 4.0 mg (as10% solution in sterile water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg 

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 250

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 251

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum  4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to  5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Example 252

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Example 253

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP 50 mg/mlGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF q.s.

Example 254

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

Example 255

Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

The sustained release formulations of this disclosure are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols). Theresulting tablets may be coated with an optional film-forming agent, foridentification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from about 1% to 10%, or from about 2% and 4% of thetablet weight. Suitable film-forming agents are well known to the artand include hydroxypropyl methylcellulose, cationic methacrylatecopolymers (dimethylaminoethyl methacrylate/methyl-butyl methacrylatecopolymers—Eudragit® E—Röhm. Pharma), and the like. These film-formingagents may optionally contain colorants, plasticizers, and othersupplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Example 256

Activity testing is conducted in the Examples below using methodsdescribed herein and those well known in the art.

Sodium Current Screening Assays:

The late sodium current (Late INa) and peak sodium current (Peak INa)assays are performed on an automated electrophysiology platform, QPatch16× (Sophion Bioscience, Copenhagen, Denmark), which uses the whole cellpatch clamp technique to measure currents through the cell membrane ofup to 16 cells at a time. The assay uses an HEK293 (human embryonickidney) cell line heterologously expressing the wild-type human cardiacsodium channel, hNa_(v)1.5, purchased from Millipore (Billerica, Mass.).No beta subunits were coexpressed with the Na channel alpha subunit.Cells are maintained with standard tissue culture procedures and stablechannel expression is maintained with 400 μg/mL Geneticin in the culturemedium. Cells isolated for use on QPatch are incubated for 5 minutes inDetachin 1× (Genlantis, San Diego, USA) at 37° C. to ensure that 80-90%of the cells are single and not part of a cell cluster. Experiments arecarried out at 23-25° C.

For both the Late INa and Peak INa assays, series resistancecompensation is set to 100% and series resistance and whole-cellcompensation are performed automatically. Currents are digitized at 25kHz and low-pass filtered at 12 kHz and 10 kHz for the late and peak INaassays, respectively. Currents through open sodium channels areautomatically recorded and stored in the Sophion Bioscience Oracledatabase (Sophion Bioscience, Copehagen, Denmark). Analysis is performedusing QPatch Assay and database software and data are compiled in Excel.

Compound stocks are routinely made by the Gilead Sample Bank in plasticvials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, whencompounds are not soluble in DMSO, they are made in 100% ethanol. Stocksare sonicated as necessary. The extracellular solution for screeningLate INa is composed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mMMgCl₂ and 5 mM HEPES with pH adjusted to 7.4 using NaOH. Theintracellular solution used to perfuse the inside of the cells for boththe Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mMEGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are dilutedin extracellular solution to 1 μM in glass vials and then transferred toglass well plates before robotic addition to the cells. The 0Naextracellular solution used at the end of each experiment for the LateINa and Peak INa assays to measure baseline current contains: 140 mMN-methyl-D-glucamine; 4 mM KCl; 1.8 mM CaCl₂; 0.75 mM MgCl₂; 5 mM HEPESand pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

For the Late INa assay, sodium channels are activated every 10 seconds(0.1 Hz) by depolarizing the cell membrane to −20 mV for 250milliseconds (ms) from a holding potential of −120 mV. In response to a−20 mV voltage step, typical hNa_(v)1.5 sodium currents activate rapidlyto a peak negative current and then inactivate nearly completely within3-4 ms.

All compounds were tested to determine their activity in blocking thelate sodium current. Late INa was generated by adding 10 μM Tefluthrin(pyrethroid) to the extracellular solution while recording Na currents.To confirm the block of late I_(Na) observed using the automatedscreening method, a second late I_(Na) enhancer (ATX-II) and the manualpatch clamp method were used. ATX-II and tefluthrin occupy distinct,non-overlapping binding sites and modify Na⁺ channel functiondifferently to increase late I_(Na). All compounds tested to date havebeen found to inhibit the enhanced late I_(Na) caused by either lateI_(Na) enhancer. For the purposes of the screening, late INa is definedas the mean current between 225 ms and 250 ms after stepping to −20 mVto activate Na channels. After establishing the whole cell recordingconfiguration, late INa activator is added to each well 4 times over a16-17 minute period so that the late component of the Na current reachesa stable value. Compounds were then added (typically at 1 μM), in thepresence of late INa activator, with 3 additions over the course of 7 or8 minutes. Measurements were made at the end of exposure to the thirdcompound addition and values were normalized to the current level whenall Na⁺ was removed from the extracellular solution after two additionsof 0Na-ECF. Results are reported as percent block of late INa. Whentested in the assay disclosed above with 10 μM Tefluthrin activatinglate INa, Compound II-3 of Example 10 inhibited (or reduced) the latesodium current by 53% (see table 1 for additional compound data).

Peak INa Screening Assay:

Compounds were also evaluated for their effect in several other assays,including their effect on Peak INa. Good separation between theconcentrations of test compound to reduce late and peak I_(Na) isbeneficial to enable separation of the desired effect to reduce lateI_(Na)-induced electrical and mechanical dysfunction from the undesiredeffect to reduce peak I_(Na), which can lead to slowing or block ofconduction of electrical excitation in the heart. It is contemplatedthat the compounds of Formula I avoid significant block of peak INa.Since the peak INa in the cells used herein can be very large,introducing artifacts in the recording, the concentration of Na⁺ in thebath can be reduced to 20 mM and a nonpermeant cation added tocompensate for the Na⁺ that was removed to maintain the osmolarity andionic strength of the solution (see solution details below). Analysis ofpeak INa generally requires correction for rundown before determiningthe % block of peak current by the tested compound.

A separate Peak INa screening assay was developed to allow assessment ofthe effect of compounds on peak INa at both low and high stimulationfrequencies in order to identify compounds that are highly selective forblock of late INa but do not block peak INa. A low stimulation frequencyof 0.1 Hz was used to determine the effect of the test compound when thechannel spent most of the time in the resting (closed) state andprovides information about Tonic Block (TB). A higher stimulationfrequency (3 Hz) was used to measure block of the channel when it spentmore time in the activated and inactivated states and provided a measureof Use-Dependent Block (UDB). Use-dependent block refers to theaccumulation of block with increased frequency of channel activation.Block of cardiac peak I_(Na) by compounds of this invention is increasedwith an increase in the frequency of stimulation from 0.1 to 1-5 Hz(frequencies encountered either in the normal heart or duringtachycardia). It is therefore expected that reduction of peak I_(Na) bycompounds of this invention will be greater at high heart rates, such asthose during tachyarrhythmias, than at normal heart rates. As aconsequence, compounds of this invention may reduce Na⁺ and Ca²⁺overload due to late INa and abnormal electrical activity and electricalconduction in myocardium that is arrhythmic, especially during ischemia.

The −100 mV holding potential and the 3 Hz stimulation frequency werechosen so that the benchmark compound would have a small but detectableeffect under experimental conditions, allowing for direct comparison ofnew compounds with the benchmark. The extracellular solution forscreening Peak INa is composed of: 20 mM NaCl, 120 mM N-methyl-Dglucamine, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂ and 5 mM HEPES with pHadjusted to 7.4 using HCl. The intracellular solution used for the PeakINa assay is the same as outlined for the Late INa assay (see above).

For the peak INa assay, Na⁺ channels were activated by depolarizing thecell membrane to 0 mV for 20 ms from a holding potential of −100 mV.After establishing the whole cell recording configuration, channels werestimulated to open with low frequency stimulation (0.1 Hz) for 7 minutesso that the recording can be monitored and the extent to which therecording has stabilized can be assessed. After this stabilizationperiod the stimulation frequency was increased to 3 Hz for 2 minutes andthen returned to 0.1 Hz. Since 3 Hz stimulation causes a small decreasein the peak current even in the absence of compound, this internalcontrol was used for each cell, when no compound is present, to correctthe results from 3 Hz stimulation when compound is present. Following 3Hz stimulation under control conditions, the cell is allowed to recoverfor 200 seconds before compound is added. The test compound tested at 1or 3 μM (depending on the % block of late INa at 1 μM) was added 3 timesat 60 second intervals, while stimulating the channels to open at 0.1 Hzto monitor the progression of TB. After the third compound addition, a320 second wait period was imposed to allow for equilibration before thesecond period of 3 Hz stimulation begins. TB was measured before thesecond period of 3 Hz stimulation. Both TB and UDB were analyzed byincorporating rundown correction for the peak INa and UDB was calculatedby compensating for the small use-dependent effect of the stimulationprotocol on peak INa in the absence of compound. Compound II-3 ofExample 10 exhibited peak INa TB of 19% and UDB of 10%, both measured at1 μM. This demonstrates the selectivity of Compound II-3 to block lateINa compared to peak INa and suggests that Compound II-3 should showminimal to no effects on conduction through the heart (which is drivenby peak INa) at concentrations that effectively block late INa (seetable 1 for additional compound data).

hERG Screening Assay:

Compounds were also tested for their effect to block the hERG K⁺channel. At least a 3-5-fold separation, preferably 10 fold separation,of IC₅₀ values for compounds to inhibit late I_(Na) (more potent) andhERG (less potent) indicates that a compound is unlikely to cause QTprolongation and/or proarrhythmic effects at concentrations needed toreduce late I_(Na).

Compounds were screened to test their activity in blocking the hERGpotassium channel at AVIVA Biosciences (San Deigo, Calif., USA). ThehERG channel is heterologously expressed in a CHO (Chinese HamsterOvary) cell line. Cells were maintained with standard tissue cultureprocedures and stable channel expression was maintained with 500 μg/mLG418 in the culture medium. Cells were harvested for testing on thePatchXpress 7000A automated patch clamp with Accumax (Innovative CellTechnologies, San Diego, Calif.) to isolate single cells.

The following solutions were used for electrophysiological recordings.The external solution contained: 2 mM CaCl₂; 2 mM MgCl₂; 4 mM KCl; 150mM NaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with 1M NaOH; osmolarity,˜310 mOsm). The internal solution contained: 140 mM KCl, 10 mM MgCl₂, 6mM EGTA, 5 mM HEPES, 5 mM ATP (pH adjusted to 7.25 with KOH; osmolarity,˜295 mOsm).

hERG channels were activated when the voltage was first stepped to −50mV for 300 ms from the −80 mV holding potential and then stepped to +20mV for 5 seconds. At +20 mV the channels open and then largelyinactivate, so the currents are relatively small. Upon returning to −50mV from +20 mV, hERG currents transiently become much larger asinactivation is rapidly removed and then the channel closes. The firststep to −50 mV for 300 ms was used as a baseline for measuring the peakamplitude during the step to −50 mV after channel activation. The peaktail current at −50 mV was measured both under control conditions andafter addition of compound, each cell serving as its own control.

All compounds were prepared as 10 mM DMSO stocks in glass vials. Stocksolutions were mixed by vigorous vortexing and sonication for about 2minutes at room temperature. For testing, compounds were diluted inglass vials using an intermediate dilution step in pure DMSO and thenfurther diluted to working concentrations in external solution.Dilutions were prepared no longer than 20 minutes before use.

For the electrophysiological recordings, after achieving the whole-cellconfiguration, cells were monitored for 90 seconds to assess stabilityand washed with external solution for 66 seconds. The voltage protocoldescribed above was then applied to the cells every 12 seconds andthroughout the whole procedure. Only cells with stable recordingparameters and meeting specified health criteria were allowed to enterthe compound addition procedure.

External solution containing 0.1% DMSO (vehicle) was applied to thecells first to establish the control peak current amplitude. Afterallowing the current to stabilize for 3 to 5 minutes, 1 μM and then 10μM test compounds were applied. Each compound concentration was added 4times and cells were kept in test solution until the effect of thecompound reached steady state or for a maximum of 12 minutes. Afteraddition of test compound, a positive control (1 μM Cisapride) was addedand must block >95% of the current for the experiment to be consideredvalid. Washout in the external solution compartment was performed untilthe recovery of the current reached steady state. Data were analyzedusing DataXpress software and its associated SQL server database,Clampfit (Molecular Devices, Inc., Sunnyvale) and Origin 7 (OriginlabCorp.) When tested in the assay disclosed above, Compound II-3 ofExample 10 inhibited (or reduced) the activity of the hERG potassiumchannel by 15.5% at 1 μM and 24.5% at 10 μM (see table 2 for additionalcompound data).

The compounds were tested using the above described assay methods. Dataare obtained by testing the listed compounds at 1 μM concentration inthe late and peak INa assays (and other concentrations as needed) and at1 μM and 10 μM for the hERG channel assay.

Microsomal Stability Assay

The micorsomal stability assay is generally performed as follows.

Format: 15 compounds (and 1 control verapamil) in 3 different species induplicate sets

General conditions:

Substrate: 3 uM

Protein concentration: 0.5 mg/mL (for dog, rat, and human livermicrosomes)

Cofactor: 1×NADPH-Regenerating system

Time-points: 2, 12, 25, 45, and 65 minutes

Reaction composition (in each incubation well):

5 uL compound (150 uM stock solution, 25:75 DMSO:H2O) 25 uL NRS solution6.25 uL 20 mg/mL liver microsomes 213.75 uL 100 mM KPO4, pH 7.4 250 uLtotal volume

TECAN program: Microsomal_Stability; Microsome_S9_Standard

Sample preparation: 25 uL at each timepoint is added to plate with 225uL quenching solution (50% MeOH, 25% ACN, 25% H2O, and 50 nM testcompound). After plates are vortexed, centrifuge for 30 minutes.

“Ideal” numbers to use for setup:

Compound plate: take 6 uL of 10 mM stock in DMSO and dilute with 394 uL25:75 DMSO:H2O to make a 150 uM stock solution. Use tall plate and addan additional 300 uL 25:75 DMSO:H2O to the third column for thestandard-making program. Shake well before use. Place this plate in“coolstack 1”.

Fill the water jug in the back of TECAN and then turn on TECAN andassociated cooling systems. Run through the “Flush” maintenance programand let system initialize. Standard plate: Fill 1 trough with buffer andplace in trough 3, 1 trough with 70% MeoH and place in trough 2, 1trough with Quench and place in trough 1. Label one tall plate as“Standards” and place in position 1. Place “compound plate” in position2. Run the “Microsome_S9_Standards” program.

After the standard program is complete, label 5 tall plates for each ofthe 5 time-points and place them in the correct positions on the TECANcountertop. Fill the 3 “Quench” troughs 90% full with the quenchingsolution (located in the fridge across from TECAN) and place it inpositions 1, 2, and 3. Run the “Microsomal Stability” program throughthe quenching portion (steps 1-52).

While the quenching filling portion of the program is running, preparemicrosomes and cofactor.

Microsomal solutions: take 400 uL of 20 mg/mL microsomes and add to13,680 uL 100 mM KPO4 buffer. Using an 8-channel, add 650 uL of thissolution to the designated two columns on a short plate. The ordershould be dog microsomes in columns 1 and 2, rat microsomes in columns 3and 4, and human microsomes in columns 5 and 6. Keep on ice before use.Place this plate in incubator 1 on the TECAN countertop.

Cofactor solution: mix 3000 uL Solution A, 600 uL Solution B, and 2400uL 100 mM KPO4 buffer in 15 mL tube/10 mL glass vial and pour solutioninto the “Cofactor” trough and put in position 3.

Remove the quenching troughs and place the cofactor trough in “position3”. Also fill up another trough with the 70:30 MeOH:H2O wash mixture andplace in “position 2”. Place the original compound plate in “coolstack1”. Place a 96-well Costar assay block on the TeShake. Once everythingis setup correctly, submit the remaining portions of the MicrosomalStability script (steps 53-312).

The assay results suggests that the compounds tested showed activity asmodulators of late sodium current, for example by inhibiting (orreducing) the late sodium current. Data are shown in Table 1 below forthose compounds that inhibit Late INa by at least 15% at the 1 μMconcentration.

TABLE 1 Late I_(Na) Assay results Peak Peak MS MS MS Late I_(Na) TB UDBRat Dog Human No. 1 μM 1 μM 1 μM THalf THalf THalf II-3 53 19 10 249 303336 II-4 41 9 4 135 61 270 II-6 43 144 123 164 II-7 75 10 4 10 II-10 21II-12 21 II-13 67 25 36 149 II-14 68 7 1 375 284 236 II-15 71 19 23 33II-16 76 102 31 74 II-17 61 11 7 24 50 101 II-18 66 15 13 49 74 130II-21 70 II-22 21 II-23 23 II-24 60 19 24 324 219 >395 II-25 50 9 2 298117 363 II-26 47 14 5 80 67 382 II-28 19 II-29 52 44 67 27 99 51 II-3264 16 21 237 36 392 II-33 26 II-34 48 27 34 2 2 2 II-36 43 7 8 108 124157 II-38 33 298 68 >395 II-39 16 II-40 48 15 29 2 2 2 II-41 25 16 80 28II-42 23 II-44 47 10 4 97 283 167 II-47 44 6 4 71 24 339 II-50 30 49 159165 II-51 35 197 93 >395 II-52 32 118 76 319 II-53 29 >395 646 >395II-54 52 5 8 176 28 329 II-55 58 7 3 2 2 14 II-56 22 II-57 38 2 4 2II-58 25 II-59 22 II-60 32 >395 356 362 II-63 46 23 50 31 36 34 II-64 433 9 16 7 11 II-65 19 II-66 39 181 >395 >395 II-67 47 12 7 >395 270 >395II-71 25 94 78 75 II-72 31 8 6 11 II-73 45 6 1 29 5 16 II-75 53 11 7 7585 371 II-79 54 II-80 42 8 7 34 85 49 II-84 34 51 98 107 II-95 36 121169 280 II-96 51 10 5 34 81 84 II-97 54 12 7 24 63 206 II-98 41 16 34 31II-99 47 9 0 42 62 128 II-100 50 15 2 35 76 52 III-2 40 222 68 333 III-342 104 122 >395 III-5 44 56 66 30 III-6 18 III-8 19 III-9 57 15 15 81 27100 III-10 33 18 18 41 III-11 30 III-12 21 III-14 39 55 77 251 III-17 4922 28 34 III-18 37 20 23 25 III-19 56 14 19 72 129 130 III-20 28 54 6141 III-22 35 86 191 252 III-23 51 6 12 42 209 254 III-24 28 9 18 13III-25 16 III-26 26 III-27 52 15 15 43 83 268 III-28 75 103 51 170III-29 58 10 9 26 18 19 III-30 56 11 12 70 167 205 III-31 27 III-32 5318 23 12 16 20 III-34 32 41 46 50 III-35 38 296 85 >395 III-36 39 32 3146 III-37 50 7 4 96 37 157 III-38 52 9 11 24 31 54 III-39 47 7 0 30 1444 III-40 51 4 2 62 56 152 III-41 24 IV-3 37 219 54 366 IV-6 49 12 7 190158 280 IV-9 42 243 356 >395 V-2 17 V-11 22 V-12 26 11 5 9 VII-1 55 7 144 114 >395 VIII-1 52 35 26 211 210 125 VIII-3 58 21 12 227 164 285VIII-7 22 152 392 221 VIII-13 20 VIII-18 54 VIII-19 61 VIII-20 62VIII-21 58 VIII-22 45 VIII-23 48 IX-1 32 150 157 >395 IX-2 40 106 88 65IX-3 29 355 320 304 IX-4 20 IX-5 20 IX-6 62 28 37 272 313 54 IX-7 46 1217 >395 >395 >395 IX-11 44 17 22 348 332 145 IX-17 39 302 >395 257 IX-2229 IX-23 27 IX-24 19 IX-25 57 28 33 170 97 320 IX-26 15 IX-27 18 IX-2824 IX-29 45 10 12 48 138 33 IX-30 20 IX-31 25 IX-32 29 IX-33 21 IX-34 16IX-36 20 IX-39 30 281 256 >395 IX-41 27 IX-42 25 IX-44 27 IX-48 31 37149 80 IX-50 29 9 96 61 IX-52 26 IX-53 33 28 93 198 IX-56 28 IX-57 44 106 132 245 159 IX-59 17 IX-77 22 IX-80 40 7 197 170 IX-88 25 IX-89 33 192177 125 IX-90 27 IX-91 16 IX-92 17 IX-93 15 IX-94 33 IX-95 25 IX-98 27IX-101 15 IX-102 27 IX-104 20 IX-105 43 6 3 14 74 35 IX-106 21 IX-107 24IX-108 30 302 370 245 IX-111 27 IX-112 18 IX-113 17 IX-114 20 IX-116 29IX-119 15 IX-122 36 IX-123 17 IX-124 40 106 88 65 X-1 47 14 22 58 107 74X-2 55 14 17 137 164 142 X-3 67 31 35 45 137 36 X-4 52 27 25 122 126 103X-5 57 12 35 57 55 48 X-6 69 35 32 46 120 38 X-9 67 39 31 47 75 70

The assay results shown in the above Table suggest that compounds testedshowed activity as modulators of late sodium current, for example byinhibiting (or reducing) the late sodium current.

In some embodiments the effects of a compound of Formula I are specificfor the late sodium current and show little or no activity with respectto one or more other ion channels. Thus, in some embodiments, a compoundhaving an activity of reducing late sodium current will also exhibitlittle or no activity with regard to the peak sodium current. Inparticular embodiments, a compound having an activity of reducing latesodium current will also exhibit little or no activity with regard tothe hERG potassium channel.

L-Type Ca2+Channel Assay—ChanTest:

Selected compounds were screened for block of the cardiac L-type Ca²⁺channel (hCav1.2, encoded by the human CACNA1C gene and coexpressed withthe beta 2 subunit, encoded by the human CACNB2 gene and alpha2delta1,encoded by the CACNA2D1 gene). The Ca²⁺ channel is heterologouslyexpressed in a CHO (Chinese Hamster Ovary) cell line. Cells aremaintained following standard tissue culture procedures and stablechannel expression is maintained with appropriate selection antibioticsin the culture medium. Cells are harvested for testing on thePatchXpress automated patch clamp (Model 7000A, Molecular Devices,Sunnyvale, Calif.) by washing twice with Hank's Balanced Salt Solution,treating the cells with trypsin and re-suspending cells in culturemedium (4-6×10⁶ cells in 20 mL). Cells in suspension are allowed torecover for 10 minutes in a tissue culture incubator set at 37° C. in ahumidified 95% air, 5% CO₂ atmosphere.

The following solutions are used for electrophysiological recordings.The external solution contains (mM): 137 NaCl, 4 KCl, 1.8 CaCl₂, 1MgCl₂, 10 Glucose, 10 HEPES (pH 7.4 with NaOH). The internal solutioncontains (mM): 130 Cs Aspartate, 5 MgCl₂, 10 EGTA, 4 ATP, 0.5 GTP, 10HEPES, (pH adjusted to 7.2 with N-methyl-D-glucamine).

Vehicle is applied to naive cells (n≧2, where n=the number cells), for a5-10 minute exposure interval. Each solution exchange is performed inquadruplicate. At the end of each experiment, a saturating concentrationof nifedipine (10 μM) is added to block hCav1.2 current. Leak current isdigitally subtracted from the total membrane current record.

Test compound stock solutions are prepared by addition of dimethylsulfoxide (DMSO) and stored frozen. Each test compound DMSO stock issonicated (Model 2510/5510, Branson Ultrasonics, Danbury, Conn.), atambient room temperature for at least 20 minutes to facilitatedissolution. Test compound concentrations are prepared fresh daily bydiluting stock solutions into the standard extracellular physiologicalsaline solution (see above). The maximum percent of DMSO added withcompound is 0.1%. All test compound and control solutions are placed ina glass-lined 96-well compound plate before loading on PatchXpress.

Two concentrations (1, 10 μM) of each test compound are applied at five(5) minute intervals via disposable polyethylene micropipette tips tonave cells (n≧2, where n=the number cells/concentration). Each testcompound concentration is added to the cell in quadruplicate. Totalduration of exposure to each test compound concentration is 5 minutes.

Onset and steady state block of hCav1.2 (α1C/β2/α2δ channels is measuredusing a stimulus voltage pattern consisting of a depolarizing test pulse(duration, 200 ms; amplitude, 10 mV) at 10 s intervals from a −80 mVholding potential. Peak current is measured during a step to 10 mV.

Example 257

Compounds of this invention that block cardiac late INa may also mediateUDB of other Na⁺ channel isoforms including the major Na⁺ channelisoforms in peripheral nervous system pain fibers, Na_(v)1.7 and 1.8.Compounds of this invention that block these channels may also be usefulto decrease neuropathic pain.

In particular embodiments, a compound will exhibit a high selectivityfor the late sodium current modulatory activity as compared to theactivity in one or more other ion channels. The selectivity of acompound may be determined by determining the percentage reduction inlate sodium current due to the compound, as measured by the assaydescribed above. The percentage reduction in one other ion channelactivity, such as the hERG potassium channel, due to the compound isdetermined as described above. The selectivity is determined by takingthe ratio of (percentage reduction in late sodium current) to(percentage reduction in one other ion channel activity). The assaysconducted to measure activities in this regard should be performed asdescribed above, with the compound at a concentration of 10 μM (or atthe upper limit of solubility, if less). In particular embodiments, theselectivity of a compound of the disclosure will be at least 5:1, e.g.at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1,at least 12:1, at least 15:1, at least 20:1, or at least 25:1, whencomparing the percentage reduction in late sodium current versuspercentage reduction of one of the peak sodium current, the hERGpotassium channel current. Selectivity data can be calculated based onthe values provided in the Examples above.

Evidence supports a role for the tetrodotoxin-sensitive Na_(v)1.7 in thepathogenesis of pain. In this assay, using whole-cell patch-clamptechnique, the effects of compounds of the invention on hNa_(v)1.7(hNa_(v)1.7+β1 subunits) peak Na⁺ current (I_(Na)) are tested asdescribed previously (Rajamani et al, 2009). Cells are continuouslymaintained using MEM (Gibco-Invitrogen, Carlsbad, Calif.) supplementedwith 10% heat inactivated fetal bovine serum, 1%penicillin-streptomycin, 600 μg/mL geneticin (Gibco-Invitrogen), 2 μg/mLblastocydin (Calbiochem, N.J., USA), and are incubated at 37° C. in anatmosphere of 5% CO₂ in air. For recording hNav1.7 I_(Na), HEK293 cellsare superfused with an extracellular solution containing (in mM): 140NaCl, 3KCl, 10 HEPES, 10 glucose, 1 MgCl₂, 1 CaCl₂, pH 7.4 (with NaOH).Patch pipettes are filled with an internal solution containing (in mM):140 CsF, 10 NaCl, 1 EGTA, 10 HEPES, pH 7.3 (with CsOH).

Whole-cell I_(Na) are recorded as described previously (Rajamani et al,2009) using an Axopatch 200B amplifier (Molecular Devices, Sunnyvale,USA). Signals are filtered at 5 kHz and sampled at 20 kHz. Patchpipettes are formed using borosilicate glass (World PrecisionInstruments, Sarasota, USA) using a micropipette puller (DaganCorporation, Minneapolis, USA). The offset potential is zeroed beforethe pipette is attached to the cell and the voltages are not correctedfor the liquid junction potential. In all recordings, 75-80% of theseries resistance compensation will be achieved, thus yielding a maximumvoltage error of 5 mV and leak currents are cancelled by P/−4subtraction. pCLAMP 10.0 software (Molecular Devices) will be used togenerate voltage clamp protocols and acquire data. Hold cells at amembrane potential of −100 or −120 mV and dialyzed with pipette solutionfor 5-7 minutes before current is recorded, to avoid time-dependentshifts in Na⁺ channel gating within the first several minutes afterpatch rupture. In all experiments, the temperature of experimentalsolutions will be maintained at 20±1° C. using a CL-100 bipolartemperature controller (Warner Instruments, Hamden, USA).

Analyze data using Clampfit and Microcal Origin (MicroCal, Northampton,USA) software.

Example 258 Material and Methods

Expression of Human Na_(v)1.1 cDNA

All experiments with humanNa_(v)1.1 are conducted as described (Kahlig,2008). Briefly, expression of hNav1.1 is achieved by transienttransfection using Qiagen Superfect reagent (5.5 μg of DNA istransfected at a plasmid mass ratio of 10:1:1 for α₁:β₁: β₂). The humanβ₁ and β₂ cDNAs are cloned into plasmids containing the marker genesDsRed (DsRed-IRES2-hβ₁) or eGFP (eGFP-IRES2-hβ₂) flanking an internalribosome entry site (IRES).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT and mutant Na_(v)1.1 channels, as described previously(Kahlig, 2008). For recording hNav1.1 I_(Na), HEK293 cells aresuperfused with solution containing (in mM): 145 NaCl, 4 KCl, 1.8 CaCl₂,1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 310mOsmol/kg. The pipette solution contains (in mM): 110 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 with an osmolarity of 300mOsmol/kg. Cells are allowed to stabilize for 10 min after establishmentof the whole-cell configuration before current is measured. Seriesresistance is compensated 90% to assure that the command potential isreached within microseconds with a voltage error <2 mV. Leak currentsare subtracted by using an online P/4 procedure and all currents arelow-pass Bessel filtered at 5 kHz and digitized at 50 kHz.

For use-dependent studies, cells are stimulated with depolarizing pulsetrains (−10 mV, 5 ms, 300 pulses, 10 and 25 Hz) from a holding potentialof −120 mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak and persistent currents are evaluated in response to a 200ms depolarization to −10 mV (0.2 Hz) following digital subtraction ofcurrents recorded in the presence and absence of 0.5 μM tetrodotoxin(TTX). Persistent current is calculated during the final 10 ms of the200 ms step. Data analysis is performed using Clampfit 9.2 (AxonInstruments, Union City, Calif., U.S.A), Excel 2002 (Microsoft, Seattle,Wash., U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, Mass., U.S.A)software. Results are presented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion. Whereappropriate, concentration inhibition curves are fit with the Hillequation: I/I_(max)=1/[1+10̂(log IC₅₀−I)*k], where IC₅₀ is theconcentration that produces half inhibition and k is the Hill slopefactor.

Solutions containing the compounds of the disclosure are perfused forthree minutes prior to current recordings to allow equilibrium (tonic)drug block. Tonic block of peak current is measured from thissteady-state condition. Use-dependent block of peak current is measuredduring pulse number 300 of the pulse train, (−10 mV, 5 ms, 300 pulses,10 Hz) from a holding potential of −120 mV. Two sequential pulse trainstimulations are averaged to obtain mean current traces for eachrecording condition.

In Vivo Pharmacology

Jugular vein cannulated male Sprague Dawley rats (250-350 g, CharlesRiver Laboratories, Hollister, Calif.) are used to study brainpenetration of the compounds of the disclosure in vivo. Animal use isapproved by the Institutional Animal Care and Use Committee, GileadSciences. Three rats per group are infused intravenously with thecompound of the disclosure in saline at 85.5 μg/kg/min. After 1, 2.5 or5 h animals are sacrificed for plasma and brain collection, andconcentrations of the compound of the disclosure are measured by liquidchromatography coupled with tandem mass spectrometry (LC-MS/MS). Braintissue is homogenated in 1% 2N HCl acidified 5% sodium fluoride (finalhomogenate is diluted 3-fold). Plasma and brain homogenate samples (50μl) are precipitated along with deuterated D3-Formula I as an internalstandard, vortexed and centrifuged. The supernatant (50 μL) istransferred and diluted with water (450 μl) prior to injection (10 μl).High performance liquid chromatography was performed using a ShimadzuLC-10AD liquid chromatograph and a Luna C18(2), 3 μm, 20×2.0 mm columnwith a mobile phase consisting of water containing 0.1% formic acid(solution A) and acetonitrile (solution B) carried out under isocraticconditions (75% solution A, 25% solution B; flow rate 0.300 ml/min).Mass spectrometric analyses are performed using an API3000 massspectrometer (Applied Biosystems, Foster City, Calif.) operating inpositive ion mode with MRM transition 428.1>98. Brain-to-plasma ratiosare calculated for each sample as ng compound/g brain divided by ngcompound/ml plasma.

Results

Using the above methods it may be demonstrated that the compound of thedisclosure have the ability to inhibit WT-Na_(v)1.1 and a panel ofNa_(v)1.1 mutant channels associated with the epilepsy and migrainesyndromes GEFS+, SMEI and FHM3 suggesting the ability of the compoundsof the disclosure to preferentially block the abnormal increasedpersistent current carried by these mutant channels. The ability of thecompounds of the disclosure to cross the blood brain barrier may also beestablished using the above methods.

Example 259 Material and Methods

Expression of Human Na_(v)1.2 cDNA

Wild-type (WT) cDNA stably transfected in Chinese hamster ovary (CHO)cells is used to record I_(Na). Unless otherwise noted, all reagents arepurchased from Sigma-Aldrich (St Louis, Mo., U.S.A.).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT. Briefly, the pipette solution consists of (in mM) 110CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 and osmolarityof 300 mOsmol/kg. The bath (control) solution contains in (mM): 145NaCl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of7.35 and osmolarity of 310 mOsmol/kg. Cells are allowed to stabilize for10 min after establishment of the whole-cell configuration beforecurrent is measured. Series resistance is compensated 90% to assure thatthe command potential is reached within microseconds with a voltageerror <2 mV. Leak currents are subtracted by using an online P/4procedure and all currents are low-pass Bessel filtered at 5 kHz anddigitized at 50 kHz.

For clarity, representative ramp currents are low pass filtered off-lineat 50 Hz. Specific voltage-clamp protocols assessing channel activation,fast inactivation and availability during repetitive stimulation areused. Results are presented as mean±SEM

Tonic block of peak current is measured using a step to −10 mV (20 ms)from a holding potential of −120 mV (0.2 Hz). Use-dependent block ofpeak current is measured during pulse number 300 of a pulse train (−10mV, 5 ms, 300 pulses, 10 Hz or 25 Hz) from a holding potential of −120mV. Two sequential pulse train stimulations are averaged to obtain meancurrent traces for each recording condition, which are then used foroffline subtraction and analysis.

For use-dependent studies, cells are stimulated with depolarizing pulsetrains (−10 mV, 5 ms, 300 pulses, 10 and 25 Hz) from a holding potentialof −120 mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak current is evaluated in response to a 20 ms depolarizationto −10 mV (0.2 Hz). Data analysis is performed using Clampfit 9.2 (AxonInstruments, Union City, Calif., U.S.A), Excel 2002 (Microsoft, Seattle,Wash., U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, Mass., U.S.A)software. Results are presented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion.

Solutions are perfused for three minutes prior to current recordings toallow equilibrium (tonic) drug block. Tonic block of peak currents ismeasured from this steady-state condition. Three sequential currenttraces are averaged to obtain a mean current for each recording. Themean current traces are utilized for offline analysis. Use-dependentblock of peak current is measured during pulse number 300 of the pulsetrain, (−10 mV, 5 ms, 300 pulses, 10 Hz) from a holding potential of−120 mV. Two sequential pulse train stimulations are averaged to obtainmean current traces for each recording condition, which are then usedfor offline subtraction and analysis. Where appropriate, concentrationinhibition curves are fit with the Hill equation: I/I_(max)=1/[1+10̂(logIC₅₀−I)*k], where IC₅₀ is the concentration that produces halfinhibition and k is the Hill slope factor.

Results

Using the above assay it may be shown that the compounds of thedisclosure have the ability to inhibit WT-Na_(v)1.2 demonstrating theability of the compounds of the disclosure to preferentially block anabnormal increased persistent current carried by this channel.

TABLE 2 NA_(v)1.1*- NA_(v)1.2*- CHAN CHAN NA_(v)1.5*- NA_(v)1.5*- TEST-TEST- RHEART NA_(v)1.5*- PEAK- PEAK- UDB- UDB- MAPD₉₀ No. LATE- TB-UDB-3 HZ- 10 HZ- 10 HZ- ATX* HERG* II-3  53 19 10 −6 −3.2 −36 16 II-1468 7 1 19.5 −0.7 −56 <10 II-17 61 11 7 42 II-18 66 15 13 30 II-32 64 1621 21 16.9 −57 45 II-36 43 7 8 7.9 10.9 21 II-38 33 −1 8 58 II-40 48 1529 81 II-54 52 5 8 23 II-55 58 7 3 II-60 32 −28 31 II-66 39 23 II-67 4712 7 −58 41 II-95 36 −0.5 −8.2 <10 III-2 40 27.6 5 6 III-5 44 9.3 5.5 13III-9 57 15 15 7.1 3.5 −53 37 III- 56 14 19 19.3 −6 23 19 III- 75 40.528.8 −40 51 28 III- 38 17 35 IV-6 49 12 7 3.1 7.1 <10 IV-9 42 −6.5 8 <10VIII- 52 35 26 4.4 16 −84 1 VIII- 58 21 12 3.1 11.7 −57 <10 3 VIII- 2212.1 18.2 <10 7 VIII- 62 27 23 11 17.6 −62 <10 20 IX-1 32 −5.9 3.8 −6 17IX- 40 2.6 7.5 −18 124 IX-3 29 2.9 −4.1 −26 14 IX-7 46 12 17 2.025 8.625−45 <10 IX- 44 17 22 11 IX- 39 1.5 10.4 −35 76 17 IX- 57 28 32 25 IX- 4510 12 29 IX- 30 1.5 16.8 −22 35 39 IX- 44 10 6 57 IX- 43 6 3 105 IX- 30108 *% inhibition at 1 μM

Example 260 Ischemia-Induced ST Segment Elevation in AnesthetizedRabbits

This study was undertaken to determine the anti-ischemic effects ofcompounds of the present invention in an in vivo rabbit model.

Methods

Female New Zealand rabbits (3.0-4.0 kg) were purchased from WesternOregon Rabbitry. Animals were housed on a 12-h light and dark cycle andreceived standard laboratory chow and water. All experiments wereperformed in accordance with the Guide for the Care and Use ofLaboratory Animals published by The National Research Council and withthe experimental protocol approved by the Institutional Animal CareCommittee of Gilead Sciences, Inc.

Rabbits were anesthetized with ketamine (35 mg/kg) and xylazine (5mg/kg) intramuscular injection (im). A tracheotomy was performed and thetrachea was intubated with an endotracheal tube. The animal wasventilated with room air supplemented with oxygen using a pressurecontrol animal ventilator (Kent Scientific Corp., Torrington, Conn.) ata respiratory rate of 40 strokes/min and peak inspiration pressure of 10mmH₂O, which was adjusted to keep blood gases and pH within thephysiological range (iSTAT clinic analyzer, Heska Corp.; Waukesha,Wis.). The left femoral artery was cannulated for the measurement ofblood pressure (BP). Blood samples were also withdrawn from femoralartery. The right external jugular vein was cannulated for drug/vehicleadministration. Needle electrodes were inserted subcutaneously into thelimbs for recording of the surface electrocardiogram (ECG). The heartwas exposed via an incision in the 4^(th) intercostal space (4^(th)and/or 5^(th) ribs were cut for a clear surgical vision). The chest wasopened and a pericardial cradle was formed using 4 retractors. Acoronary artery occluder, comprised of a snare made of 5 cm PE-10 tubingwith a 6-0 Prolene polypropylene suture in it, was placed loosely aroundthe left anterior descending artery (LAD) at its origin. Two unipolarelectrodes, made with teflon coated silver wire attached to a smallpatch of filter paper, were attached on the surface of the ischemic andnormal regions of the left ventricle to record epicardialelectrocardiogram. Reference electrodes were placed in the open incisionof the neck. The body temperature of the animal was monitored via arectal thermometer and maintained at 37-40° C. by adjusting the surfacetemperature of the surgical table. Regional ischemia (15 min) wasinduced by ligating the LAD followed by 15 min of reperfusion caused byreleasing the ligation. The heart was excised at the end of theexperiment and the LAD was re-ligated. The ischemic area was visualizedby perfusing the heart with 1% Evans blue in saline and calculated as apercentage of total ventricular weight. Rabbits with ischemic area lessthan 10% or larger than 25% were excluded from the analysis. Animalswere randomly assigned to vehicle and test compound groups. Testcompounds was dissolved in 5% NMP, 30% PG, 45% PEG 400 and 20%de-ionized water (dH₂O). Test compound was given as an iv bolus at 0.1,0.2 and 0.4 mg/kg. After 30 min of dosing, the heart was subjected to 15min of ischemia followed by 15 min of reperfusion.

Results

The compound of Example II-14 dose-dependently prevented theischemia-induced ST elevation. The area under curve (AUC) for the STsegment height was reduced (vs. control) by 19% and 75% at 0.3 and 0.7μM plasma concentration of compound of Example II-14. At the plasmaconcentration levels studied, compound of Example II-14 had nosignificant effect on blood pressure (BP), heart rate (HR) and ECGintervals prior to the ischemia. The data suggests the compound ofExample II-14 prevents ischemia-induced myocardial electricaldysfunction in a dose-dependent manner.

Example 261 Rabbit Heart (RHEART) MAPD₉₀ ATX Materials and Methods

New Zealand White female rabbits weighing 2.5-3.5 kg were used in thisstudy. Animal use was approved by the Institutional Animal Care and UseCommittee of Gilead Sciences, Palo Alto. Each rabbit was sedated usingan intramuscular administration of a mixture of 6 mg/kg xylazine and 40mg/kg ketamine, and then anesthetized by i.v. administration of 15 mg/kgketamine+4 mg/kg xylazine in 1.5 ml saline via the marginal ear vein.After anesthesia was complete, the thorax was quickly opened. The heartwas excised and placed in a modified Krebs-Henseleit (K-H) solution atroom temperature. The K-H solution contained (in mmol/L): NaCl 118, KCl2.8, KH₂PO₄ 1.2, CaCl₂ 2.5, MgSO₄ 0.5, pyruvate 2.0, glucose 5.5,Na₂EDTA 0.57 and NaHCO₃ 25. The solution was continuously gassed with95% 02 and 5% CO₂, warmed to 36-36.5° C., and adjusted to pH 7.4. Theaorta was rapidly catheterized and the heart was perfused by the methodof Langendorff with K-H solution at a rate of 20 mL/min, using a rollerpump (Gilson Minipuls3).

Coronary perfusion pressure was measured with a Biopac MP 150 pressuretransducer from a side port of the aortic catheter and continuouslyrecorded. To facilitate exit of fluid from the chamber of the leftventricle (LV), the leaflets of the mitral valve were trimmed with finespring-handled scissors. The right atrial wall was partially removed toallow access to the right ventricular septum.

Complete AV block was induced by thermoablation of the AV nodal area.The spontaneous ventricular rate (i.e., the ventricular escape rhythm)was a few beats per minute after successful AV nodal ablation. A bipolarTeflon-coated electrode was placed on the right ventricular septum topace the heart. Electrical stimuli 3 ms in width and 3-fold thresholdamplitude were delivered to the pacing electrode at a frequency of 1 Hzthroughout an experiment using a Grass S48 stimulator. After initiationof ventricular pacing, a 30-40 min delay was allowed for heart rhythmand perfusion pressure to achieve a steady state, an essentialexperimental condition for recording a good quality monophasic actionpotential (MAP).

Assay

The total duration of the experimental protocol was limited to 2.5 h,the time during which the preparation exhibited good stability. Inexperiments wherein compound concentration-response data were obtained,the compound was administered in increasing concentrations sequentiallywith no washout period between concentrations.

Responses were recorded after the effect of a given test drug (or drugconcentration) had achieved a steady-state. Continuous left ventricularMAP and 12-lead pseudo-electrocardiogram (ECG) signals were recordedusing electrodes from Harvard Apparatus, Inc. An MAP electrode wasplaced on the epicardial left ventricular free wall below the level ofatrial-ventricular valves to record MAP signals from the base of theheart left ventricle. Electrode signals were amplified and displayed onan oscilloscope for visual monitoring throughout an experiment. The MAPduration (from onset of depolarization to 100% repolarization) wasmeasured using an on-screen caliper throughout each drug infusionperiod, to ensure that each response to drug had achieved a steady statebefore a drug concentration was changed. Electronic signals were savedon a computer hard disk for subsequent analysis. The 12-lead pseudo-ECGwas generated using an isolated-heart ECG apparatus (Harvard Apparatus)attached to Biopac amplifier system. MAPs, ECGs, and coronary perfusionpressure signals were appropriately amplified, filtered, and digitizedin real time using a Biopac MP 150 signal processor and displayed on acomputer screen. All signals were saved on a computer hard disk forsubsequent analysis. Original MAP profiles were transferred into thesoftware program Spike-II (Cambridge Electronic Design) to measure theduration of the MAP at the level at which repolarization is 90%completed (MAPD₉₀).

Data Analysis

Data were plotted and analyzed using Prism version 5 (Graph PadSoftware, San Diego, Calif.) and expressed as mean±SEM. The significanceof differences of measurements before and after interventions in thesame heart was determined by repeated measure one-way analysis ofvariance (ANOVA) followed by Student-Newman-Kaul's test. When treatmentvalues were obtained from different groups of hearts that wereelectrically paced at 1 Hz, two-way ANOVA with repeated measures wasused. A paired or un-paired student t test was used to determine thestatistical difference between values of two means obtained from thesame or different experiments, respectively (see results in Table 2).

What is claimed is: 1-41. (canceled)
 42. A compound of Formula I:

wherein: the dotted line represents an optional double bond; Y is—C(R⁵)₂— or —C(O)—; X¹ is N and X² is CR³, and the dotted line is adouble bond; or Y is —C(O)—; Q is a covalent bond or C₂₋₄ alkynylene; R¹is C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, heterocyclyl or heteroaryl;wherein said C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, heterocyclyl orheteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,—N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—S(O)₂—R²²,—S(O)₂—R²⁰, S(O)₂—N(R²⁰)(R²²) C-₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₆ cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein saidC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl,heteroaryl or heterocyclyl are optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;R² is —R⁶, C₁₋₆ alkylene-R⁶, C₂₋₆ alkenylene-R⁶, —C₂₋₆ alkynylene-R⁶,L-R⁶, -L-C₁₋₆ alkylene-R⁶, —C₁₋₆ alkylene-L-R⁶ or —C₁₋₆ alkylene-L-C₁₋₆alkylene-R⁶; L is —O—, —S—, —C(O)—, —S(O)₂—, —NR²⁰S(O)₂—, —S(O)₂NR²⁰—,—C(O)NR²⁰— or —NR²⁰C(O)—; and R² is -L-R⁶, -L-C₁₋₆ alkylene-R⁶, —C₁₋₆alkylene-L-R⁶ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁶; each R³ isindependently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl orheterocyclyl; wherein said C₁₋₆ alkyl is optionally substituted withone, two or three substituents independently selected from the groupconsisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said C₃₋₆ cycloalkyl, aryl, heterocyclyl andheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; and wherein said C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl, aryl,heterocyclyl and heteroaryl are optionally further substituted with one,two or three substituents independently selected from the groupconsisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₄alkoxy, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰, C₃₋₆cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₃₋₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O) R²⁰, C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein said C₃₋₆, cycloalkyl, aryl,heterocyclyl or heteroaryl are optionally further substituted with one,two or three substituents independently selected from the groupconsisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl, C₃₋₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and wherein said C₁₋₆ alkyl,aralkyl, C₃₋₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of hydroxyl, halo, —NO₂,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;each R⁵ is independently hydrogen or C₁₋₆ alkyl; R⁶ is C₃₋₆ cycloalkyl,aryl, heteroaryl or heterocyclyl; wherein said C₃₋₆ cycloalkyl, aryl,heteroaryl or heterocyclyl are optionally substituted with one, two orthree substituents independently selected from the group consisting ofC₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂, C₃₋₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,—N(R²⁰)—C(O)—R²², —C(O)—²⁰, C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰,—CN and —O—R²⁰; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heterocyclyl or heteroaryl are optionally further substituted with one,two or three substituents independently selected from the groupconsisting of halo, —NO₂, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of C₁₋₆ alkyl, halo, aryl, —NO₂, —CF₃,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰and —O—R²⁰; R²⁰ and R²² are in each instance independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, heterocyclyl,aryl or heteroaryl; and wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, heterocyclyl, aryl or heteroaryl areoptionally substituted with one, two or three substituents independentlyselected from the group consisting of hydroxyl, halo, C₁₋₄ alkyl,aralkyl, —N(R²⁶)(R²⁸), aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃ alkoxy,—CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, —C(O)—R²⁶, —C(O)—OR²⁶, aryl, C₃₋₆cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said aralkyl,heterocyclyl or heteroaryl is optionally further substituted with C₁₋₄alkyl, —CF₃, aryl or C₃₋₆ cycloalkyl; or when R²⁰ and R²² are attachedto a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic orheteroaryl ring which is then optionally substituted with one, two orthree substituents independently selected from the group consisting ofhydroxyl, halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy,heteroaryloxy, substituted amino, aminoacyl, —NO₂, —S(O)₂—R²⁶, —CN, C₁₋₃alkoxy, hydroxymethyl, —CF₃, —OCF₃, aryl, heteroaryl and C₃₋₆cycloalkyl; and R²⁶ and R²⁸ are each independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₃₋₆ cycloalkyl,aryl and heteroaryl; and wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, arylor heteroaryl may be further substituted with from to 3 substituentsindependently selected from the group consisting of hydroxyl, halo, C₁₋₄alkoxy, —CF₃, —OCF₃ and C₃₋₆ cycloalkyl; or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof.
 43. The compound ofclaim 42, wherein Q is a bond.
 44. The compound of claim 42, wherein R²is —R⁶, —C₁₋₆ alkylene-R⁶, -L-R⁶, -L-C₁₋₆ alkylene-R⁶ or —C₁₋₆alkylene-L-R⁶; L is —O—, —C(O)—, —S(O)₂—, —S(O)₂NR²⁰— or —C(O)NR²⁰—; andR⁶ is cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein saidcycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, halo, cycloalkyl, aryl, heteroaryl,—N(R²⁰)(R²²), —C(O)—OR²⁰, —S(O)₂—R²⁰, —CN and —O—R²⁰; wherein said C₁₋₆alkyl or heteroaryl are optionally further substituted with one, two orthree substituents independently selected from the group consisting ofhalo, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)—OR²⁰ and —O—R²⁰,and wherein said heteroaryl is optionally further substituted with one,two or three C₁₋₆ alkyl.
 45. The compound of claim 44, wherein R² is


46. The compound of claim 42, wherein R¹ is aryl or heteroaryl; whereinsaid aryl or heteroaryl are optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, —O—R²⁰, C₁₋₄ alkyl, cycloalkyl and heterocyclyl; and wherein saidC₁₋₄ alkyl or cycloalkyl are optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo and —CN.
 47. The compound of claim 42, wherein R¹ is aryl orheteroaryl optionally substituted with trifluoromethoxy ortrifluoromethyl.
 48. The compound of claim 42, wherein the compound is2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-benzyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-phenethyl-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-1H-pyrrol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((4-methyl-1,25-oxadiazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one6-((1-oxo-7-(4-(trifluoromethoxy)phenyl)phthalazin-2(1H)-yl)methyl)picolinonitrile2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(3-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(6-methylpyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((4,6-dimethoxypyrimidin-2-0)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((4,6-dimethylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((4-cyclopropylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(1H-1,2,4-triazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one 2-((4-(cyclopropylmethoxy)pyrimidin-2-yl)methyl4-(trifluoromethoxy)phenyl)phthalazin-1 (2H)-one2(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(4-cyclopropylpyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenylphthalazin-1(2H)-one2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(4(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2(2-(pyrimidin-4-yl)ethyl)-7-(4-(trifluoromethoxy)phenylphthalazin-1(2H)-one2(2-(5-chloropyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(1H-pyrazol-1-yl)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-(2H)-one2-(2-(pyrazin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one2-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one24(5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-oneor a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof.
 49. A compound of Formula IB:

wherein: the dotted line represents a double bond; R¹ is aryl orheteroaryl; wherein said aryl or heteroaryl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of halo, —NO₂, CN, —SF₅, —Si(CH₃)₃, —O—CF₃, -O—R²⁰,—S—R²⁰, —C(O)—R²⁰, C(O)OH, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),—N(R²⁰)—C(O)R²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²),C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl; and wherein said alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl are optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halo, —NO₂, —O—CF₃, —O—CHF₂, phenyl, heterocyclyl,heteroaryl, C₁₋₄ alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; R² is hydrogen, C₁₋₁₅alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶, —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰,cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein said alkyl,alkoxy, cycloalkyl, and heterocyclyl are optionally substituted withone, two, or three substituents independently selected from the groupconsisting of hydroxyl, alkyl, alkoxy, alkynyl, halo, NO₂, —O—CF₃,—O—CHF₂, aryl, heterocyclyl, heteroaryl, cycloalkyl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)N(R²⁰)(R²²), —CN, oxo, and —O—R²⁰; whereinsaid alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl areoptionally further substituted with one, two, or three substituentsindependently selected from the group consisting of hydroxyl, halo,—NO₂, —CF₃, —O—CF₃, C₁₋₆ alkyl, C₁₋₄ alkoxy, benzyl, aryl, heterocyclyl,heteroaryl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,—C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and wherein said C₁₋₆ alkyl, C₁₋₄alkoxy, benzyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, areoptionally further substituted with one, two, or three substituentsindependently selected from the group consisting of hydroxyl, halo,—NO₂, —O—CF₃, —CF₃, —O—CHF₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰,—C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and —O—R²⁰; Q is a covalent bond orC₂₋₄ alkynylene; X¹ is N and X² is CR³; R³ is hydrogen, C₁₋₁₅ alkyl,C₁₋₄ alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein saidalkyl is optionally substituted with one, two, or three substituentsindependently selected from the group consisting of halo, —NO₂, aryl,heterocyclyl, heteroaryl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; wherein saidcycloalkyl, aryl, heterocyclyl, or heteroaryl are optionally furthersubstituted with one, two, or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, benzyl, aryl,heterocyclyl, heteroaryl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)N(R²⁰)(R²²), —CN, and —O—R²⁰, and wherein said C₁₋₆alkyl, benzyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, areoptionally further substituted with one, two, or three substituentsindependently selected from the group consisting of halo, —NO₂,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰;R⁴ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,—C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰ cycloalkyl, aryl, heteroaryl, orheterocyclyl; wherein said alkyl is optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halo, NO₂, aryl, heterocyclyl, heteroaryl,cycloalkyl)-N(R²⁰)(R²²), —C(O)—R²⁰, C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN,and —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl, or heteroarylare optionally further substituted with one, two, or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, benzyl, aryl; heterocyclyl, heteroaryl, cycloalkyl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, and —O—R²⁰; and whereinsaid C₁₋₆ alkyl, benzyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, areoptionally further substituted with one, two, or three substituentsindependently selected from the group consisting of halo, —NO₂,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—O—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, and—O—R²⁰; R²⁰ and R²² are in each instance independently selected from thegroup consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, C₂-C₁₅alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and wherein thealkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of hydroxyl, halo, C₁₋₄alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroarylamide, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,—C(O)—NH₂, aryl, cycloalkyl, and heteroaryl; wherein said heteroaryl isoptionally further substituted with C₁₋₄ alkyl, or cycloalkyl; or whenR²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may jointo form a heterocyclic or heteroaryl ring which is then optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of hydroxyl, halo, alkyl, benzyl, phenyl,phenoxy, benzyloxy, monoalkylamino, dialkylamino, alkyl amide, arylamide, heteroaryl amide, NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃,aryl, heteroaryl and cycloalkyl; R²⁵ is in each instance independently acovalent bond or C₁-C₃ alkylene optionally substituted with one or twoC₁-C₃ alkyl groups; and R²⁶ and R²⁸ are in each instance independentlyselected from the group consisting of hydrogen, alkyl, and cycloalkyl;and wherein the alkyl, phenyl and cycloalkyl may be further substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of hydroxyl, halo, C₁₋₄ alkoxy, —CF₃, and —OCF₃; or apharmaceutically acceptable salt, ester, hydrate, solvate, polymorph,and/or prodrug thereof.
 50. A pharmaceutical composition comprising acompound according to claim 42, and one or more pharmaceuticallyacceptable carriers.
 51. A method of treating a disease state in amammal that is alleviable by treatment with an agent capable of reducinglate sodium current, comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of
 42. 52. Themethod of claim 51, wherein the disease state is a cardiovasculardisease selected from one or more of atrial and ventricular arrhythmias,heart failure (including congestive heart failure, diastolic heartfailure, systolic heart failure, acute heart failure), Prinzmetal's(variant) angina, stable and unstable angina, exercise induced angina,congestive heart disease, ischemia, recurrent ischemia, reperfusioninjury, myocardial infarction, acute coronary syndrome, peripheralarterial disease, pulmonary hypertension, and intermittent claudication.53. The method of claim 51, wherein the disease state is diabetes ordiabetic peripheral neuropathy.
 54. The method of claim 51, wherein thedisease state results in one or more of neuropathic pain, epilepsy,seizures, or paralysis.